Genetics of non-syndromic hearing loss in the Middle East

International Journal of Pediatric Otorhinolaryngology xxx (2014) xxx–xxx

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PEDOT-7265; No. of Pages 11

Review Article

Genetics of non-syndromic hearing loss in the Middle East

Hossein Najmabadi *, Kimia Kahrizi

Genetics Research Centre (GRC), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2. Genes involved in cochlear homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.1. Gap junctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.1.1. Gap junction protein, beta-2 gene (DFNB1A) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.1.2. Gap junction protein, beta-6 gene (DFNB1B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.1.3. Gap junction protein, beta-3 gene (DFNA2B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2. Tight junctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.1. Claudin 14 gene (DFNB29) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.2. Marvel domain-containing protein 2 gene (DFNB49) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.3. Other genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.3.1. Pendrin gene (DFNB4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.3.2. POU domain, class 4, transcription factor 3 gene (DFNA15) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.3.3. Estrogen-related receptor beta gene (DFNB35) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.3.4. Calcium- and integrin-binding protein 2 ?gene (DFNB48) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.3.5. Barttin gene (DFNB73) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3. Genes implicated in cellular organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.1. Myosins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.1.1. Myosin 3A gene (DFNB30) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.1.2. Myosin 6 gene (DFNB37). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.1.3. Myosin 7A gene (DFNB2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.1.4. Myosin 15A gene (DFNB3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

A R T I C L E I N F O

Article history:

Received 18 July 2014

Received in revised form 24 August 2014

Accepted 25 August 2014

Available online xxx

Keywords:

ADNSHL

ARNSHL

Gene frequencies

Hereditary hearing loss

Middle East

Mutation

A B S T R A C T

Hearing impairment is the most common sensory disorder, present 1 in every 500 newborns. About 80%

of genetic HL is classified as non-syndromic deafness. To date, over 115 non-syndromic loci have been

identified of which fifty associated with autosomal recessive non-syndromic hearing loss (ARNSHL). In

this review article, we represent the 40 genes function and contribution to genetic deafness in different

Middle Eastern populations as well as gene frequencies and mutation spectrum. The wide variety of

mutations have so far detected in 19 countries reflects the heterogeneity of the genes involved in HL in

this region. The deafness genes can cause dysfunction of cochlear homeostasis, cellular organization,

neuronal transmission, cell growth, differentiation, and survival, some coding for tectorial membrane-

associated proteins, and the remaining with unknown functions. Non-syndromic deafness is highly

heterogeneous and mutations in the GJB2 are responsible for almost 30–50% in northwest to as low as 0–

5% in south and southeast of the Middle East, it remain as major gene in ARNSHL in Middle East. The other

genes contributing to AR/ADNSHL in some countries have been determined while for many other

countries in the Middle East have not been studied or little study has been done. With the advancement

of next generation sequencing one could expect in next coming year many of the remaining genes to be

determine and to understand their function in the inner ear.

� 2014 Elsevier Ireland Ltd. All rights reserved.

Contents lists available at ScienceDirect

International Journal of Pediatric Otorhinolaryngology

jo ur n al ho m ep ag e: ww w.els evier . c om / lo cat e/ i jp o r l

* Corresponding author at: University of Social Welfare and Rehabilitation Sciences, Daneshjoo Blvd., Koodakyar St., Evin, Tehran 1985713834, Iran. Tel.: +98 21 22180138;

fax: +98 21 22180138.

E-mail address: [email protected] (H. Najmabadi).

Please cite this article in press as: H. Najmabadi, K. Kahrizi, Genetics of non-syndromic hearing loss in the Middle East, Int. J. Pediatr.Otorhinolaryngol. (2014), http://dx.doi.org/10.1016/j.ijporl.2014.08.036

http://dx.doi.org/10.1016/j.ijporl.2014.08.036

0165-5876/� 2014 Elsevier Ireland Ltd. All rights reserved.


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H. Najmabadi, K. Kahrizi / International Journal of Pediatric Otorhinolaryngology xxx (2014) xxx–xxx2

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3.2. Other genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.2.1. Otocadherin gene (DFNB12) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.2.2. Protocadherin 15 gene (DFNB23) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.2.3. Radixin gene (DFNB24) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.2.4. Trio- and F-actin-binding protein (DFNB28) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.2.5. Whirlin gene (DFNB31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4. Genes coding for tectorial membrane-associated proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.1. Stereocilin gene (DFNB16) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.2. a-Tectorin gene (DFNB21) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.3. Otoancorin gene (DFNB22) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.4. Collagen type XI alpha-2 gene (DFNB53). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

5. Genes involved in neuronal transmission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

5.1. Otoferlin gene (DFNB9) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

5.2. Pejvakin gene (DFNB59) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

6. Genes implicated in cell growth, differentiation, and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

6.1. Hepatocyte growth factor gene (DFNB39) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

6.2. Serpin peptidase inhibitor, clade B (ovalbumin), member 6 gene (DFNB91) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7. Genes with other or unknown functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.1. Transmembrane inner-ear expressed gene (DFNB6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.2. Transmembrane cochlear-expressed gene 1 (DFNB7/11) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.3. Transmembrane protease, serine 3 gene (DFNB8/10) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.4. GIPC PDZ domain-containing family member 3 gene (DFNB15/72/95) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.5. Glutaredoxin gene (DFNB25) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.6. Immunoglobin-like domain-containing receptor 1 gene (DFNB42) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.7. Leucine-rich transmembrane o-methyltransferase gene (DFNB63) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.8. Lipoma HMGIC fusion partnerlike 5 gene (DFNB67) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.9. Methionine sulfoxide reductase B3 gene (DFNB74) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.10. Lipoxygenase homology domain-containing 1 gene (DFNB77). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.11. Taperin gene (DFNB79). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.12. G protein signaling modulator 2 gene (DFNB82) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

7.13. Protein-tyrosine phosphatase receptor-type Q gene (DFNB84) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

8. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

9. Future direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

1. Introduction

Deafness or hearing loss (HL) can be due to genetic orenvironmental causes or a combination of both. The genetic HLis classified as syndromic or non-syndromic (NS). Like manydisorders in the syndromic HL, the pathology varies widely,however in non-syndromic HL (NSHL), the defect is generallysensorineural. Majority of hereditary HL is classified as non-syndromic [1]. ARNSHL is genetically heterogeneous and is themost common form of inherited HL. Autosomal recessive genes areresponsible for about 80% of the cases of hereditary NSHL, with 40different genes identified to date (http://hereditaryhearinglos-s.org/), whereas this amount reduced to 27 genes for autosomaldominant NSHL. Of these genes responsible for deafness, many ofthe encoded proteins have been shown to be expressed within thecochlea and can be grouped into functional categories that affecthair-cell structure, extracellular matrix, ion homeostasis, tran-scription factors, and miscellaneous. It is believed autosomalrecessive disorder are 2–3 times more common in this part ofworld because of consanguinity marriages compare to Europeanand American population where there is no or little consanguinityexist. In the other hand the number of autosomal dominant genesremain the same. The fact that families in the Middle East areusually large and you can see many affected children in thefamilies, therefore, they are ideal for autozygosity mapping andthis is why many of AR genes have been identified in thesepopulation. Mutations in many of these genes have also been foundin other western countries and have contributed to understand thefunction of these genes. This extreme genetic heterogeneitysuggests that there are many different genes that can malfunctionwithin the inner ear to cause HL. Majority of these genes (40) havebeen identified in families from the Middle East (supplementary

Please cite this article in press as: H. Najmabadi, K. Kahrizi, GeneticsOtorhinolaryngol. (2014), http://dx.doi.org/10.1016/j.ijporl.2014.08.0

Table 1). The Middle East is a region that comprises 39 countriesand encompasses Western Asia and part of Northern Africa, lies atthe juncture of Eurasia and Africa and of the Mediterranean Sea andthe Indian Ocean. The Middle East and North Africa has apopulation of about 331 million according to a World Bank reportreleased in 2011, or nearly as many people as the United States.Saudi Arabia is the largest of the core countries of the Middle Eastin area. Bahrain, an island nation in the Persian Gulf, is the smallestof the Middle Eastern states [2]. The most populous Middle Easterncountries are Turkey, Egypt, Pakistan and Iran, each with more than60 million people. The Persian Gulf states of Bahrain and Qatarhave the smallest populations, about 400,000 each. The MiddleEast is today home to numerous long established ethnic groups,including Arabs, Turks, Persians, Jews/Israelis, Kurds, Assyrians(Chaldo-Assyrians), Arameans-Syriacs, etc. The most importanttrouble which Middle East faced is explosive population growthand high consanguineous marriage rate in this region; whichincreased the risk of recurrence of autosomal recessive forms ofgenetic disorders such as deafness. With a population projected togrow from 350 million to 1.1 billion by 2050, the greater MiddleEast is one of the fastest growing regions in the world [3]. TheMiddle East has uniquely high rates of consanguineous marriageamong the world’s regions. To determine the incidence of HLamong consanguineous marriages in Saudi Arabia, two epidemio-logical surveys were carried out 10 years apart; 6421 subjects fromRiyadh City and 9540 from all other parts of the Kingdom of SaudiArabia. The survey has conducted among 1st and 2nd cousins andthe results showed that about 66% of the 1st cousin offspring hadHL and those from a 2nd cousin relationship had an incidence of37%, concluded that in developing nations, cultural issues affectthe incidence of hearing impairment [4]. According to the WHOglobal estimation on prevalence of HL reported in 2012, there were

of non-syndromic hearing loss in the Middle East, Int. J. Pediatr.36

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360 million persons in the world with disabling HL (5.3% of theworld’s population) of whom 328 million (91%) are adults(183 million males, 145 million females) and 32 million (9%) arechildren [5]. This report emphasized that the prevalence of HL isgreatest in South Asia (27%), East Asia (22%), and Asia Pacific (10%).Sub-Saharan Africa, Latin America and Caribbean, Central/EastEurope and Central Asia each with a prevalence of 9% wereafterward, while this amount reduced to 3% in Middle East andNorth Africa. The prevalence of disabling HL in children is greatestin South Asia, Asia Pacific and Sub-Saharan Africa. Six million of183 million male adults with HL worldwide in 2012 lived in MiddleEast and North Africa with a prevalence of 4.1%, and this amountsfor female adults were 4 out of 145 million (2.9%), and for children1.2 out of 31.9 million (0.9%) [5].

The aim of this review was to describe the function of thesegenes and to understand their contribution to non-syndromicgenetic deafness in Middle Eastern populations, frequencies, andfind out the heterogeneity of mutations (supplementary Table 2).

2. Genes involved in cochlear homeostasis

2.1. Gap junctions

2.1.1. Gap junction protein, beta-2 gene (DFNB1A)

Connexins are involved in the formation of gap junction andallows cell to cell communication through the plasma membraneof many different cells. The gap junction allows intercellularexchange of small molecules in the microenvironment of tissueand has an important role in intercellular communication [6]. Thefirst discovery of an autosomal recessive gene, GJB2, was reportedin 1996 [7] in a large consanguineous family of Pakistani originwith non-syndromic profound deafness (DFNB1A) that mapped to13q11–q12 and mutation in autosomal dominant form wasidentified in 1997 (DFNA3; MIM# 601544) [8]. Interestingly, threesyndromic GJB2 related deafness have also been reported as an ADpattern of inheritance. GJB2 encodes the gap-junction proteinconnexin (Cx) 26. Mutations in the GJB2 gene accounting for up to50% of cases with ARNSHL in European population [9]. This type ofHL is usually congenital and stable, with little progression, and itsseverity varies from moderate-to-profound. Up to date over 200different mutations have been reported in GJB2 gene [Human GeneMutation Database Professional Edition, accessed in June 2010].The deletion of a guanine at position 30 (c.30delG) is found to bethe most common mutation in many world population as well asmany country in the Middle East. It is mostly presented in theTurkey, north Iraq, northwest of Iran and it is much less present insouth of Iran, Pakistan, India and Arabic countries located in thesouthern part of Persian Gulf (supplementary Table 3, Figs. 1 and2). Certain Cx26 gene mutations are ethnic-specific, such as 35delGmutation prevalent in Caucasians, 167delT in Ashkenazi Jews, andW24X in Pakistan and Indian population [10]. The frequency of35delG mutation in the Middle East countries has been reportedand compared with other continents in supplementary Table 3. Thec.235delC is the second most commonly found mutation of Cx26,results in a frameshift and premature termination of the protein, isalso the most frequent deletions among Turkish, and Palestinian,but not identified in Pakistani and Arabs [11,12]. The 167delTmutation, which has a rate of 7.5% frequency in Ashkenazi Jews,has been observed in Palestinian, Syrian, Tunisian, Iranian, Turkish,and Pakistani population (supplementary Table 2). IVS1 + 1G > Awhich is splice site mutation have been detected in severalpopulations as disruptive mutation. The frequency of IVS1 + 1G > AA was found to be about 4.9% in Azeri Turks of Iran (supplementaryTable 2). Our recent study not published yet suggests that this is thesecond common mutation in Iranian population. The W77R(c.229T > C) is specific mutation in Arab population from Qatari,


and Saudi Arabia (supplementary Table 2). Two large deletions:del(GJB6-D13S1830) and del(GJB6-D13S1854) are consideredcause digenic HHL are more frequent in Spain, France, the UnitedKingdom, have been reported only in few Middle Easterncountries such as Israel and Tunisia [6]. Cx26 mutations havealso been identified in ADHL forms in Iran and Turkey(supplementary Table 2). In conclusion, more than 60 mutationsin the GJB2 gene responsible for ARNSHL have so far beenidentified in Middle East and less than 10 mutations for DFNA3Aloci (ADNSHL) (supplementary Table 3).

2.1.2. Gap junction protein, beta-6 gene (DFNB1B)

Gap junction protein beta-6 (GJB6) or connexin 30 (Cx30) genelocated on 13q12.11, comprises of 3 exons. The gap junction allowsintercellular exchange of small molecules and has an important rolein intercellular communication. Mutations in this gene can causedominant, recessive, and digenic forms of syndromic and NSHL. GJB6

missense mutations cause an inherited autosomal dominant skindisorder, hidrotic ectodermal dysplasia (Clouston syndrome) (MIM#129500), which associated with HL. Mutation in GJB6 gene was firstdetected in families with autosomal dominant, bilateral, middle tohigh frequency HL (DFNA3B, MIM# 612643) [13]. Autosomalrecessive form of mutation (DFNB1B, MIM# 612645), was firstidentified in a Spanish family with digenic inheritance of GJB2/GJB6

mutations; a 342-kb deletion at GJB6 and 35delG at GJB2 [14]. Amulticenter study showed GJB6 deletion was present in most of thescreening populations, with higher frequencies in France, Spain, andIsrael where the percentages of unexplained GJB2 heterozygotesindividuals from 16 to 20.9% after screening for the GJB6 deletionmutation. The del(GJB6-D13S1830) is a founder mutation inAshkenazi Jews and for countries in western Europe [15]. Thisdeletion was identified also in Tunisian ARNSHL patients.

2.1.3. Gap junction protein, beta-3 gene (DFNA2B)

Gap junction protein beta-3(GJB3) or connexin 31 (Cx31) genelocated on 1p34.3, comprises of 2 exons. GJB3, one of the multigenefamily gap junctions, involved in ion homeostasis of cochlear.Mutations in this gene can cause dominant and recessive anddigenic (GJB2/GJB3) forms of non-syndromic HL. Mutation in GJB3

gene was first detected in a Chinese family with autosomaldominant, bilateral, progressive sensorineural deafness (DFNA2B,MIM# 612644) [16]. A putative mutation, p.P223T, was also foundin the GJB3 gene in heterozygous form in a Turkish family with twoaffected children with ARNSHL [17].

2.2. Tight junctions

2.2.1. Claudin 14 gene (DFNB29)

Several different genes including tight junctions TRIC andCLDN14 are involved in inner ear ion homeostasis and have beenlinked to deafness. CLND14 mutations in humans cause profoundcongenital ARNSHL [18]. The CLDN14 gene mutations whichidentified in twenty six Pakistani families with severe-to-profoundARNSHL and with an allelic frequency of 6.87% in Morrocanpopulation, is not a contributor to profound deafness in Iran,Turkey, and Tunisia. An additional patient identified from Greeceaffected with sporadic NSHL (supplementary Table 2).

2.2.2. Marvel domain-containing protein 2 gene (DFNB49)

Tricellulin (TRIC) also referred to as MARVELD2, located onchromosome 5q13.2, is an integral membrane protein concentrat-ed at the vertically oriented TJ strands of tricellular contacts inwhich mutant alleles co-segregate with non-syndromic moderate-to-profound DFNB49 (MIM# 610153). Mutations of TRIC associat-ed with HL remove all or most of a conserved region in the cytosolicdomain that binds to the cytosolic scaffolding protein ZO-1 [19]. In




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general, five different homozygous mutations of TRIC in 11Pakistani families were demonstrated, which IVS4 + 2T > C, wasreported in six families. Recently, a nonsense mutation inMARVELD2 gene is identified in a consanguineous ARNSHL Iranianfamily (supplementary Table 2).

2.3. Other genes

2.3.1. Pendrin gene (DFNB4)

Pendrin, encoded by SLC26A4, is a transmembrane anionexchanger that belongs to the solute carrier 26 family and exchangeschloride, iodide, bicarbonate and formate. Mutations in SLC26A4 arethe second most frequent cause of ARNSHL. Over 100 mutations inthe SLC26A4 (PDS) gene are involved in both Pendred syndrome (PS)and NSHL (DFNB4), associated with temporal bone abnormalities.The associated phenotypic spectrum ranges from Pendred syn-drome at one extreme to isolated NSHL with enlarged vestibularaqueduct (EVA) at the other (DFNB4 locus). In many populations,mutations in the SLC26A4 gene are the major genetic cause of thesetemporal bone inner ear malformations, accounting for up to 90% ofthe typical population with PS, 80% of individuals with EVA, and thesame rate among patients with Mondini dysplasia [20]. It has beensuggested that PS is being caused by biallelic SLC26A4 mutations, andat least some cases of non-syndromic EVA being associated with asingle SLC26A4 mutation. Three different mutations found to beinvolved both in PS and in NSHL (p.L445W, p.H723R, and the IVS7-2A > G). From these the missense mutation p.L445W (c.1334T > G)has been identified in Tunisian, and Iranian families with ARNSHL(supplementary Table 2).

2.3.2. POU domain, class 4, transcription factor 3 gene (DFNA15)

POU4F3 is one of 14 transcription factors in the POUsuperfamily. All members contain two DNA-binding domains,which bind a target DNA and are involved in tissue specific generegulation. POU4F3 is a class IV POU protein and is essential for cell-specific maturation, survival and inner-ear hair cell maintenance.The gene is expressed in the cochlear and vestibular hair cells andregulates Gfi1 and Lhx3 [21]. The segregating mutations affect DNAbinding properties and cause a partial mislocalization outside thenucleus. The phenotypic consequence is HL that is highly variablein age of onset, level of progression and even audioprofile. Ingeneral, however, mid and high frequencies are affected withmoderate-to-severe HL [22]. An autosomal dominant form ofprogressive HL (DFNA15, MIM# 602459) was initially mapped to5q31 in an Israeli Jewish family through at least 5 generations [23].

2.3.3. Estrogen-related receptor beta gene (DFNB35)

ESRRB gene encodes the estrogen-related receptor protein betathat is a member of the nuclear hormone receptor (NHR) family oftranscription factors. ESRRB is essential for inner-ear developmentand function [24]. Mutations of ESRRB are causative for early-onsethearing impairment. Missense mutations are likely to affect thestructure and stability of DNA- and ligand-binding domains [24].Locus DFNB35 (MIM# 608565), located on 14q24.3, was firstmapped in large consanguineous kindred from Pakistan segregat-ing severe-to-profound ARNSHL, non-progressive prelingual deaf-ness [25]. Four mutations of ESRRB gene was identified in Turkish,Pakistani and Tunisian families located in the DNA-binding andligand-binding domains. Interestingly, ligand-binding domain ofthe ESRRB protein has been affected in 5 out of 6 mutations causingDFNB35 HL (supplementary Table 2).

2.3.4. Calcium- and integrin-binding protein 2 gene (DFNB48)

CIB2 belongs to a family of calcium and integrin-binding proteinscontaining four EF-hand domains that change conformation uponbinding Ca2+, and presumably mediate intracellular Ca2+ signaling


and plays conserved roles in calcium homeostasis [26]. The CIB2

gene contains 6 exons encoding 3 different isoforms, each affectedby the four USH1 J/DFNB48 mutations. CIB2 mutations underlieUsher syndrome 1 J (MIM# 614869) and non-syndromic deafnessDFNB48. Up to now mutations in CIB2 gene at ARNSHL locus[DFNB48] segregating in Pakistani and Turkish families [27](supplementary Table 2). Hence, CIB2 is one of the major causesof ARNSHL within the Pakistani population.

2.3.5. Barttin gene (DFNB73)

The BSND encodes barttin, an accessory subunit of renal andinner ear chloride channels. Barttin is an accessory subunit of twohuman ClC-K channels, ClC-Ka (MIM 602024) and ClC-Kb (MIM602023), which are essential for chloride reabsorption along thedistal nephron and for endolymph formation in the inner ear.Mutations of the barttin gene (BSND) have been shown to causesyndromic and non-syndromic forms of HL. Bartter syndromecomprises several closely related renal tubular disorders that canbe grouped into at least three clinical phenotypes: infantile variantof Bartter syndrome, classic Bartter syndrome, and Gitelmansyndrome [28,29]. In Middle East mutations in BSND gene atARNSHL locus (DFNB73) segregating only in Pakistani familieswith minimal renal dysfunction and interferes with chaperonefunction of barttin in intracellular trafficking [30].

3. Genes implicated in cellular organization

3.1. Myosins

Myosin genes are members of a large superfamily of genes thatencode proteins that exert mechanical forces. The myosins aremolecular motors that bind to actin filaments and move alongthem. They have many functions, including transport of intracel-lular organelles, phagocytosis, secretion, muscular contraction,and cellular movement.

3.1.1. Myosin 3A gene (DFNB30)

Myosin IIIA is an unconventional myosin of the inner ear thatcauses HL in humans. The protein is found at the tips of developingstereocilia surrounding the tip density region that may be the site ofactin polymerization and operation of the MET apparatus. MyosinIIIA is also found further down the shaft of the stereocilia [31].DFNB30 locus, located on chromosome 10p12.1, was first identifiedin an Israeli family that can be traced to the Jewish community ofMosul, Iraq [32]. In contrast to most other recessive mutations,MYO3A mutations in this locus cause late-onset, progressiveARNSHL that starts during the second decade. To explain thisunusual phenotype, it has been proposed that myosin IIIB partlycompensates for lack of myosin IIIA [31]. In the Middle Easterncountries only three mutations have been reported in Israeli Jewish-Iraq population in MYO3A gene (supplementary Table 1) [32].

3.1.2. Myosin 6 gene (DFNB37)

Myosin VI, encoded by MYO6 (located 6q14.1), is expressedmost strongly in the cuticular plate and is involved in stereociliaformation. The protein is required to attach the apical plasmamembrane to the base of stereocilia and/or anchor stereociliarootlets [33].

Several nonsense, missense, frameshift mutations in the MYO6

gene have been identified in families with bilateral, profound,congenital ARNSHL deafness linked to 6q13 (DFNB37; MIM#607821) with phenotypic variability such as vestibular dysfunctionand mild facial dysmorphism along with retinitis pigmentosa [34].Several deafness-causing mutations in MYO6 gene have beenreported from Pakistan, Israeli Jewish and Palestinian Arabs(supplementary Table 2).




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MYO7A encodes for myosin VIIA, which is ubiquitously expressedin many epithelial tissues including the inner ear and retina. In theinner ear, myosin VIIA is found in the sensory hair cells, mainly in thestereocilia but also along the lateral membrane of the cell, in thecuticular plate and in the synaptic region. In humans, mutations inMYO7A cause ADNSHL. Mutations in this gene also associated withvestibular disorders (DFNA11), profound ARNSHL (DFNB2), Ushersyndrome type 1B (USH1B) and USH3-like phenotypes. Severalhomozygous or compound heterozygous mutations in the myosin7A gene have been identified in families with autosomal recessiveprelingual deafness with phenotypic variability such as vestibulardysfunction and mild retinitis pigmentosa may be due to acombination of allelic, environmental, and genetic backgrounddifferences (supplementary Table 2). MYO7A mutations are preva-lent cause of ARNSHL and have been reported from Pakistan, Iran,Turkey, Palestinian Arabs and Israeli Jewish in Middle East(supplementary Table 2). According to our results MYO7A mutationsare less prevalent among Iranian population than Turkish with afrequency of 3.3% in GJB2-negative Turkish families [35].


The myosin 15 gene is located on chromosome 17p11.2, awidely expressed member of the myosin superfamily. The myosin-XV protein has been shown to be integral for development andelongation of the stereocilia through delivery of whirlin to the tipsof stereocilia. Whirlin binds to SH3-MYTH4-FERM-domain-con-taining region of the Myo15a protein and regulates actin filamentelongation. Additionally, myosin-XV interaction with whirlinmay play a role in cohesion of stereocilia [36]. The first report ofHL at the DFNB3 locus was from an isolated village in Indonesiawhere 2% of the population was hearing impaired [37]. MYO15A

mutations have been reported in different domains of the gene,in families from Pakistan, India, Turkey, Indonesia, Brazil andNorth America. Up to now nine different missense, nonsense anddeletional mutations have found in Iranian and Pakistani deafpopulation in MYO15A gene, with prevalence of 5.5% (8/144) inGJB2-negative Iranian families and 5% in Pakistan [37,38]. Todate, several different mutations have been reported fromseveral Middle Eastern countries including Israel, Iran, Pakistan,Palestine, Saudi Arabia, Tunisia, and Turkey, suggesting thatMYO15A is a relatively common cause of ARNSHL in this part ofworld (supplementary Table 2).

3.2. Other genes

3.2.1. Otocadherin gene (DFNB12)

Mutations in cadherin-related family, member 23 (CDHR23)gene, are responsible for both Usher syndrome and DFNB12 NSHL.CDH23 encodes cadherin 23, a putative calcium-dependentadhesion molecule required for proper morphogenesis of mechan-osensitive hair bundles of the inner-ear neurosensory cells [39],which is responsible for intercellular adhesion and for signaling.Only missense mutations of CDH23 have been observed in familieswith NSHL, whereas nonsense, frameshift, splice-site, deletion, andmissense mutations have been identified in families with Ushersyndrome [40]. Among Pakistani families six mutations and inIndian two and in a family of Jewish-Algerian descent onemutation reported in CDH23 gene (supplementary Table 2).

3.2.2. Protocadherin 15 gene (DFNB23)

PCDH15 belongs to the cadherin superfamily of calcium-dependent cell–cell adhesion molecules. Mutations in PCDH15

cause both Usher syndrome type 1F (USH1F) and severe-to-profound ARNSHL. Human PCDH15 is reported to be comprised of35 exons and encodes a variety of isoforms. Only the first 2 exons of


the human PCDH15 gene are situated in the USH1F critical regiondefined by one of the Pakistani families studied. A genotype–phenotype correlation has been proposed for PCDH15 mutations inwhich hypomorphic alleles of the gene cause ARNSHL and moresevere mutations cause Usher syndrome [41]. The first mutationsin ARNSHL reported in two consanguineous Pakistani families,mapped to DFNB23, demonstrated a missense mutation p.G262D(c.785G > A) in exon 8, which encodes part of the second of 11extracellular cadherin domains (EC) of PCDH15, and a transversionmutation p.R134G (c.400C > G) in exon 5, which encodes part ofthe first EC domain [41].

3.2.3. Radixin gene (DFNB24)

Radixin is part of the ezrin/radixin/moesin (ERM) family whichconsists of three closely related proteins that function as cross-linkers between plasma membranes and actin filaments [42].Radixin is present along the length of the hair cell stereocilia,mainly at the lower half. By linking the actin-cytoskeleton toadhesion proteins, the protein participates in the formation of themembrane-associated cytoskeleton. Radixin functions as a linkerbetween subcellular actin and the plasma membrane, the exactrole of this protein in the stereocilia of hair cells is unclear [42]. Afew frameshift, nonsense, missense and splice site mutations havebeen reported from Middle Eastern countries such as Iran andPakistan, suggesting that RDX gene is a less frequent geneparticipating in the AR causes of NSHL in this area (supplementaryTable 2).

3.2.4. Trio- and F-actin-binding protein (DFNB28)

The TRIO and filamentous actin binding protein encoded byTRIOBP colocalizes with F-actin along the length of the stereociliaand is thought to be involved in actin cytoskeletal organization.The TRIOBP gene contains 24 exons, with different isoforms, ofwhich mutations in the longest isoform are the cause of profoundARNSHL [43]. Mutations of the TRIOBP gene causing prelingual,profound ARNSHL in a Palestinian family designated DFNB28(MIM# 609823) [44]. In other study four nonsense and twoframeshift mutations were identified in ARNSHL Pakistani andIndian families (supplementary Table 2).

3.2.5. Whirlin gene (DFNB31)

Whirlin is an important scaffolding protein in the Usher proteinnetwork and links many different proteins. It is transientlyexpressed in stereocilia tips during elongation in both inner andouter hair cells and is also found at the base of stereocilia. Thecomplex that forms between whirlin and myosin XVA mayindirectly regulate actin polymerization and in this way, contrib-ute to stereocilia elongation and actin polymerization. Whirlin alsodirectly interacts with USH2A and VLGR1b, and together withvezatin, these proteins form the ankle-link complex. Whirlin alsointeracts with myosin VIIa that is present along the entire length ofthe stereocilia. In humans, WHRN mutations cause profoundARNSHL and Usher syndrome type IID. WHRN gene was firstmapped to DFNB31 (MIM# 607084) in a Palestinian consanguine-ous family from Jordan [45]. Later, a nonsense mutation in WHRN

gene identified in this family resulting in lacking the third PDZdomain (supplementary Table 2). In addition, in a consanguineousTunisian family segregating congenital profound ARNSHL, aframeshift mutation identified [46].

4. Genes coding for tectorial membrane-associated proteins

4.1. Stereocilin gene (DFNB16)

Highly specialized epithelial cells, the sensory hair cells in thecochlea, are responsible for mechano-electrical transduction and




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ultimately the perception of sound. The apical surface of each haircell contains a staircase-like bundle of mechanosensory stereocilia[47]. Recent studies on stereocilia dynamics have revealed that thestereocilia actin cytoskeleton shows continuous turnover withactin filament assembly occurring at the stereocilium tip and itsdisassembly at the base. Total actin filament renewal within thestereocilia thus occurs by a treadmilling mechanism with turnoverrates proportional to the stereocilia lengths [48].

The STRC gene, which encodes stereocilin, is expressed in thesensory hair cells and is associated with the stereocilia, the stiffmicrovilli forming the structure for mechanoreception of soundstimulation. Two frameshift mutations and a large deletion in thecopy containing 29 coding exons in two families affected byARNSHL linked to the DFNB16 locus [49]. Eight deletions have beendetected in STRC gene so far. The data suggest that STRC may be acommon contributor to inherited non-syndromic bilateral senso-rineural HL (NBSNHI) among GJB2 mutation negative probands,especially in those with mild to moderate hearing impairment[50]. Microdeletion syndrome reported in the gene with hearingloss and male infertility.

4.2. a-Tectorin gene (DFNB21)

TECTA gene encodes a-tectorin, an extracellular protein constitu-ent of the tectorial membrane and the otolithic membrane in thecochlea and vestibular system, respectively [51]. NonprogressiveARNSHL that is profound is typically associated with severe hair celldamage, or in cases of more moderate HL, damage to supportingstructures like the tectorial membrane in TECTA-associated HL(DFNB21, MIM# 602574). Mutations in TECTA gene on chromosome11q, encoding a-tectorin, are responsible for NSHL in both dominant(DFNA8/12) and recessive (DFNB21) types. Functional null alleles ofTECTA at the DFNB21 locus cause recessive, prelingual, nonprogres-sive, severe-to-profound HL. Dominant TECTA mutations (DFNA8/12)can cause either progressive or nonprogressive HL depending on theirlocation within the gene and with dominant negative effect. Severalmutations in ARNSHL patients have been reported from Lebanon, Iranand Palestine (supplementary Table 2).

4.3. Otoancorin gene (DFNB22)

The OTOA gene encodes otoancorin, which belongs to a group ofnoncollagenous glycoproteins of the acellular gels of the inner earthat specifically located at the interface between the apical surfaceof the sensory epithelia and their overlying acellular gels, and alsoentirely specific for the inner ear. OTOA gene has 28 exons spanningapproximately 82 kb, and was mapped to chromosome 16p12.2[52]. Till now, missense, splice site mutations and large deletionsreported in moderate-to-severe prelingual sensorineural HLPalestinian families and the carrier frequency of the OTOA genomicdeletion in this population estimated to be 1% [53].

4.4. Collagen type XI alpha-2 gene (DFNB53)

Mutations in the COL11A2 gene (MIM# 120290) on chromo-some 6p21.32 have been found in families with both autosomaldominant (at the DFNA13 locus) and autosomal recessive (at theDFNB53 locus) and various syndromes that include a deafnessphenotype. The first cases of autosomal recessive form of NSHLhave been reported in a consanguineous Iranian family [54]. Thehomozygosity mapping of this family has identified a novel locusfor ARNSHL on chromosome 6p21.3, which was designated asDFNB53. Mutation in COL11A2 was determined to co-segregatewith prelingual, profound HL ARNSHL [54]. All diseases associatedwith allele variants of COL11A2 including non-ocular Sticklersyndrome, OSMED syndrome and DFNA13, have a hearing


impairment phenotype [55–57]. Among the genes involve inhearing loss which have been identified so far it seems mutationsin this gene result in most variable phenotype most likely bychanging the arrangement of collagen fibrils pattern.

5. Genes involved in neuronal transmission

5.1. Otoferlin gene (DFNB9)

A gene at the DFNB9 locus on chromosome 2p is called theotoferlin gene, because its product shows homology to dysferlin, aprotein that is defective in some myopathies. OTOF encodes forotoferlin, a member of the mammalian ferlin family of membrane-anchored cytosolic proteins. The protein is probably essential forexocytosis and neurotransmitter release at the inner hair cell ribbonsynapse. OTOF mutations cause prelingual, profound ARNSHL, whichmay initially be accompanied by auditory neuropathy in about halfof cases with biallelic OTOF mutations [58]. OTOF mutations accountfor deafness in 2.3% (13/557) Pakistani families [19]. In the Spanishpopulation, p.Q829X is the most common OTOF mutation identifiedand ranks as the third most common cause of ARNSHL in this ethnicgroup [58]. OTOF gene mutations account for about 5.0% of deafpopulation in Turkey [19]. To date, over 20 different mutations havebeen reported from Middle Eastern countries (supplementaryTable 2).

5.2. Pejvakin gene (DFNB59)

Genetic mutations that lead to progressive ARNSHL are veryrare. A mutation in pejvakin gene in a consanguineous Iranianfamily with progressive ARNSHL was reported [59]. This geneencodes the cytoplasmic protein pejvakin (PJVK) [DFNB59 onchromosome 2q31.1–q31.3 (MIM# 610219)]. In patients withmutations in this gene, the onset of progressive HL is duringchildhood. This gene is expressed in hair cells, suggesting thatintrinsic defects of hair cell function may be common toprogressive ARNSHL. Mutations in PJVK gene in DFNB63 lociwhich was first identified in both Iranian family and Dfnb59 knock-in mice cause auditory neuropathy (p.R183W) [38]. Since thenseveral mutations in PJVK gene at DFNB59 locus have beenreported from Pakistani, Iranian, Palestinian, and Israeli Arabs inMiddle Eastern countries (supplementary Table 2). These findingssuggest that mutation in PJVK gene is common in the Middle East.

6. Genes implicated in cell growth, differentiation, and survival

6.1. Hepatocyte growth factor gene (DFNB39)

HGF, the gene encoding hepatocyte growth factor (MIM#142409), was first mapped to DFNB39, on chromosome 7q11.22–q21.12 in a consanguineous Pakistani family with profoundprelingual sensorineural deafness [60]. HGF is involved in a widevariety of signaling pathways in many different tissues. To date,synonymous substitution and deletions reported segregating withprofound prelingual NSARHL in Pakistani and Indian families [61].

6.2. Serpin peptidase inhibitor, clade B (ovalbumin), member 6 gene

(DFNB91)

Serpins are grouped into different phylogenic clades [62]. Inhumans, the largest clade (clade B) contains 13 largely intracellularproteins, among which are serine proteinase inhibitors andcysteine proteinase inhibitors [63]. SERPINB6 gene initiallymapped to DFNB91 in an ARNSHL consanguineous Turkish familywith progressive, age-dependent and moderate-to-severe affectedindividuals. The nonsense mutation (p.E245X) in SERPINB6 gene




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identified in this Turkish family encodes for an intracellularprotease inhibitor co-segregated as a completely penetrantautosomal-recessive trait [63]. In cohort of 49 Turkish and 144Iranian consanguineous families with non-syndromic deafness,only mutation in this gene was seen in one Turkish family [19,38].

7. Genes with other or unknown functions

7.1. Transmembrane inner-ear expressed gene (DFNB6)

TMIE gene encodes for a protein which shows no similarities toother proteins. The study of the recessive mouse mutant spinner(sr) carrying a mutation in Tmie suggests that the gene is requiredduring maturation of sensory cells and is involved in thedevelopment or maintenance of stereocilia bundles. In humans,mutations in TMIE cause autosomal recessive severe-to-profoundHL. Insertion, deletion, and three missense mutations weredescribed in five families from Pakistan and India resulting inARHL linked to DFNB6 locus on 3p21 [64]. Later, homozygousmutations in TMIE gene were found in three additional familiesfrom Pakistan, one from Jordan and eight from Turkey withARNSHL (supplementary Table 2). The prevalence of functionalTMIE variants in Pakistani families is 1.7% [65].

7.2. Transmembrane cochlear-expressed gene 1 (DFNB7/11)

Mutations of the TMC1 gene have been shown to causeautosomal dominant and recessive forms of NSHL linked to theloci DFNA36 and DFNB7/B11, respectively. An association withboth progressive and stable hearing impairment has previouslybeen reported for TMC1 [66]. It was suggested that TMC1 mightbe an ion channel or transporter which mediates K+ homeostasisin the inner ear. TMC1 gene was initially mapped to chromosome9q13–q21 in two consanguineous Indian families with pre-lingual, severe-to-profound defining the DFNB7 locus [67]. TMC1

is the sixth most common cause of recessive HL worldwide, andone of the more frequent causes of ARNSHL in populations fromthe consanguinity belt. Thirty different mutations of the TMC1

gene (GenBank accession number: NM_138691.2) have beenreported in 48 families with ARNSHL. Mutations in TMC1 are acommon cause of ARNSHL in India, Iran, Pakistan, Tunisia, andTurkey where they account for the hearing-loss phenotype in 3–6% of families [68–70]. The most common recessive mutation forHL in the TMC1 gene is p.R34X (c.100C > T) and has been shownto have arisen from two founders [68]. It accounts for over 30–40% of mutant alleles of TMC1 and occurs in populationsthroughout Middle Eastern and North Africa [69], such asPakistani, Saudi Arabian, Turkish, and Tunisian (supplementaryTable 2).

7.3. Transmembrane protease, serine 3 gene (DFNB8/10)

Transmembrane protease, serine 3 gene, is identified within theDFNB8 (MIM# 601072)/DFNB10 (MIM# 605316) [71]. TMPRSS3 isa member of the Type II Transmembrane Serine Protease family(TTSP), a class of membrane-bound proteolytic enzymes thatmediate a variety of biological processes. It is expressed in theneuron bodies of the spiral ganglion, the stria vascularis and theepithelium of the organ of Corti. The protein role is possiblethrough regulation of ENaC. ENaC is a sodium channel known to beregulated by serine protease activity therefore it affects cochlearsodium concentration. The protein contains transmembranedomain located near the N terminus; a low density lipoproteinreceptor A domain, which binds calcium and low densitylipoprotein; a scavenger receptor cysteine-rich domain that isinvolved in protein–protein interaction; and a C-terminal serine


protease domain from the S1 family of the SA clan of serine-typepeptidases for which the prototype is chymotrypsin. TMPRSS3

encodes a predicted secreted serine protease, although thededuced amino acid sequence has no signal peptide. Sixteendifferent TMPRSS3 mutations lie in all functional domains havebeen described that cause ARNSHL and were found to disrupt theproteolytic activity of TMPRSS3. Most affected persons havebilateral, severe-to-profound HL, but age of onset, severity and rateof progression are variable, with no described middle ear orvestibular deficits. The TMPRSS3 mutations in the Middle East havebeen identified in Palestinian (DFNB10), Pakistani (DFNB8),Turkish, Saudi Arabian and Tunisian deaf population (supplemen-tary Table 2).

7.4. GIPC PDZ domain-containing family member 3 gene (DFNB15/72/

95)

Autosomal recessive NSHL loci DFNB15, DFNB72 and DFNB95were all located on chromosome 19p13.3–p13.1 [72,73]. TheGIPC3 was also mapped to chromosome 19p13.3, encodes a 312amino acid protein that contains three predicted low complexityregions and a central conserved PDZ domain [74,75]. Two of thethree low complexity regions are similar in sequence among GIPCfamily members and are referred to as GIPC homology domains(GH1 and GH2). The GH2 domain of GIPC1 interacts directly withthe actin-based molecular motor myosin 6, in which mutationscause HL in humans and mice. Missense and frameshift mutationshave been reported in Indian, Dutch, Turkish, and Pakistanifamilies, which all are located in the GH1 or GH2 domains(supplementary Table 2). Recently, a novel missense mutationdetected in a Saudi Arabian family presenting severe to profoundARNSHL [76].

7.5. Glutaredoxin gene (DFNB25)

Mutations in the glutaredoxin (cysteine rich 1) gene onchromosome 4p15.3–q12 at the DFNB25 locus lead to early-onsetautosomal recessive HL in humans and mice and can be associatedwith vestibular dysfunction. A role in actin organization in haircells has been suggested because of the localization of GRXCR1 inthe hair bundle and stereocilia abnormalities in the pi mutant [77].HL in patients with GRXCR1 mutations is congenital and ismoderate to profound. Defects in GRXCR1 can be associated withboth progressive and stable HL [78]. Up to now, missense andnonsense mutations in the GRXCR1 gene have been identified inDutch and Pakistani families [78].

7.6. Immunoglobin-like domain-containing receptor 1 gene (DFNB42)

The DFNB42, which located on chromosome 3q13.33, wasoriginally mapped in a single Pakistani family [79]. The humanILDR2 maps to the DFNA7 locus on 1q24.132 and is therefore aninteresting candidate gene for autosomal-dominant deafness.ILDR1 is a gene of unknown function, but its expression in themouse cochlea and vestibule as well as in the zebrafish ear and inlateral line neuromasts supports an essential role in hearing invertebrates. To date, 15 different ILDR1 mutations includingmissense, nonsense, frameshift, and splice-site mutations as wellas a start codon mutation were found in Pakistani and IranianDFNB42-related deafness families (supplementary Table 2). Wehave reported ten of fifteen distinct ILDR1 mutations previously,five of which originated from Iran, all are nonsense, missense,frameshift, deletion, or splice site mutations predicted to introducepremature stop codons that may lead to NMD and/or proteintruncation. Thus, complete loss of ILDR1 function appears tounderlie hearing impairment in most of cases.




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7.7. Leucine-rich transmembrane o-methyltransferase gene

(DFNB63)

By genomewide linkage analysis of NSHL segregating in a largeconsanguineous Tunisian family and a consanguineous Pakistanifamily, DFNB63 was mapped on human chromosome 11q13.2–q13.3[80,81]. LRTOMT has two alternative reading frames and encodes twodifferent proteins, LRTOMT1 and LRTOMT2. Mutations of LRTOMT areassociated with congenital profound NSHL at the DFNB63 locus. Inaffected members of four unrelated families with DFNB63 fromTurkey, Tunisia, and Pakistan four different homozygous mutationswere identified in the LRTOMT gene (supplementary Table 2).Screening for LRTOMT mutations in 49 Turkish ARNSHL familiesreveals a relative frequency of 1.7% and in 80 families from Moroccothe frequency of 8.75% has reported. Mutations in LRTOMT genedefine as the second cause of HL after the GJB2 gene in the etiology ofdeafness in Moroccan population [82]. Several missense andframeshift mutations reported from Iran. Up to now eight differentmutations have been reported from Middle Eastern countriesincluding Iran, Pakistan, Tunisia, Turkey, and Morroco in whichthe most was from Iran (supplementary Table 2).

7.8. Lipoma HMGIC fusion partnerlike 5 gene (DFNB67)

LHFPL5 (alias TMHS) encodes for the tetraspan membraneprotein of hair cell stereocilia and was discovered in the recessivemouse mutant hurry-scurry (hscy), in which recessive Tmhs

mutations cause HL and vestibular dysfunction. Mutations inthe human TMHS are the cause of profound ARNSHL withoutvestibular dysfunction. DFNB67 locus was first mapped in twofamilies from Pakistan with bilateral profound HL withoutvestibular dysfunction [83]. Finding missense mutations and aone base-pair deletion in three consanguineous Turkish familieswith non-syndromic, bilateral, severe-to-profound, sensorineuralHL have provide further evidence that mutations in LHFPL5 causeARNSHL without vestibular dysfunction. A point mutation has alsodetected in a Palestinian and a Saudi Arabian family withprelingual NSHL (supplementary Table 2).

7.9. Methionine sulfoxide reductase B3 gene (DFNB74)

MSRB3 is a member of methionine sulfoxide reductases, whichcatalyze reduction of free and protein-bound methionine sulf-oxides to corresponding methionines [84]. The DFNB74 locus wasfirst mapped to chromosome 12q14.2–q15 in 3 consanguineousPakistani families with prelingual bilateral profound deafnessinherited in an autosomal recessive pattern [85]. Several transver-sion and nonsense mutations have been found in 8 Pakistanifamilies some encoding mitochondrial localization signals in theinner ear [86].

7.10. Lipoxygenase homology domain-containing 1 gene (DFNB77)

The DFNB77, which maps to chromosome 18q12–q21, was firstidentified in a five-generation consanguineous Iranian family. Weidentified a homozygous stop mutation, c.2008C > T (p.R670X), inexon 15 in all affected family members tested [87]. The human andmurine LOXHD1 proteins consist of 15 PLAT (polycystin/lipox-ygenase/a-toxin) domains, which share structural similarity toeukaryotic Ca2þ-binding C2 domains. PLAT domains are believedto be involved in targeting of proteins to the plasma membrane[87]. Homozygous mutations in the human and mouse genes forLOXHD1 lead to auditory defects, indicating that the protein isessential for normal hair cell function along the plasma membraneof stereocilia. Progression of ARNSHL has been associated withmutations in and LOXHD1 [87]. Homozygous mutation of the


LOXHD1 gene resulting in a premature stop codon (p.R1572X) innine patients of Ashkenazi Jewish origin who had severe-to-profound congenital ARNSHL represents a non-progressive deaf-ness in case (supplementary Table 2).

7.11. Taperin gene (DFNB79)

TPRN encodes taperin, which is concentrated at the taper regionof stereocilia. Within the taper, the peripheral filaments of theactin core have pointed ends terminating at different levels,whereas actin filaments in the center of stereocilia core continueuninterrupted through the taper region. Taperin modulate actindynamics through direct or indirect interaction with pointed endsof actin filaments specifically within the hair cell stereocilia [88].TPRN was found as the gene mutated in DFNB79 in 4 consanguine-ous Pakistani families as well as a large consanguineous Moroccanfamily [88,89], a form of ARNSHL linked to chromosome 9q34.3. InPakistani families truncating mutations and in Moroccan familyand a Dutch family with DFNB79 homozygous loss of functionmutations in the TPRN gene were found (supplementary Table 2).

7.12. G protein signaling modulator 2 gene (DFNB82)

GPSM2, also known as LGN (Leu-Gly-Asnrepeat-enrichedprotein), is a 677 amino acid, G protein signaling modulator[90]. The establishment of polarity during cellular differentiationand the maintenance of proper polarity requires GPSM2 and thatloss of GPSM2 function by premature truncation of the GPSM2protein would lead to abnormal orientation of hair bundles andhence to aberrant hair cell transduction and HL [91]. DFNB82initially was mapped on chromosome 1p13.3 in a consanguineousPalestinian family with ARNSHL [92]. Later two nonsensemutations found in this family and a consanguineous Turkishfamily [93].

7.13. Protein-tyrosine phosphatase receptor-type Q gene (DFNB84)

DFNB84 locus was first mapped to chromosome 12q15 [94],and very later it has been noted that the PTPRQ gene mapped tochromosome 12q21.31 and contains 58 exons [95]. DifferentPTPRQ isoforms are encoded with a varying number of fibronectintype 3 (FN3) domains, a transmembrane domain, and a phospha-tase domain [95]. PTPRQ and Myosin VI are thought to form acomplex that is essential for tethering of the membrane to thecytoskeleton in the tapered ankle region of stereocilia [96].Nonsense and missense mutations in PTPRQ gene were initiallydetected in a non-consanguineous Dutch family and a consan-guineous Moroccan family with congenital, progressive, andmoderate to profound ARNSHL [95] accompanied by vestibulardysfunction in all affected individuals. Also a nonsense mutation inPTPRQ detected in a consanguineous Palestinian family withmoderate to severe prelingual HL [97].

8. Discussion

WHO has estimated that in 2001 [23], 250 million persons in theworld have disabling hearing impairment; the burden is estimatedto be approximately twice as large in developing countries as indeveloped countries [98]. Based on epidemiological data, at least onechild in 1000 is born with HL in developed countries and more than50% of prelingual deafness cases are found to have hereditary HL.Prevalence of hearing impairment in children estimated to 0.05–0.23% in developed countries, 0.2–0.42 in developing countries[99]. This prevalence is high among Middle Eastern countries suchas Saudi Arabia and Kenya with a frequency of 7.7 and 2.2,respectively [99]. Therefore, identification and understanding the




G Model


function of these genes are essential for selecting the optimaltreatment of patients with HL, carrier detection, and preimplantgenetic diagnosis in this region. Several genes discovered in theauditory system illustrate that mutations in one gene may giverise to quite variable phenotypes. For example, mutations in asingle gene can lead to both syndromic and NSHL (as is thecase with COL11A2, MYO7A, CDH23, BSND, and SLC26A4 (PDS)).Moreover, mutations in a single gene can cause both dominantand recessive forms of NSHL (e.g., GJB2 for both DFNA3 (MIM#601544) and DFNB1 (MIM# 220290)), TECTA for DFNA8/12 andDFNB21, TMC1 for DFNA36 DFNB7/11. These phenotypic diversitydemonstrate how the type of mutation, the position of themutation within the gene, and allelic combinations (i.e.,compound heterozygosity) can affect the overall clinical presen-tation in sensorineural deafness individuals. This article reviewedthe genetic characteristics of the deafness genes contribute toautosomal dominant and autosomal recessive NSHL in MiddleEastern population and represents all of the 340 reported variantsin this region (for 14 remaining genes which have only fewmutations reported in one country of Middle East including BSND,COL11A2, GJB3, GPSM2, GRXCR1, HGF, MSRB3, MYO3A, MYO6, OTOA,POU4F3, PTPRQ, SERPINB6, STRC see the supplement). Many ofthese genes have been identified in families from this part of theworld using homozygosity mapping and followed by convention-al or next generation sequencing. Therefore, recruitment ofadditional families from Middle Eastern countries will help ingene discovery as well as determine the genetic spectrum, andshould be continued. Reported mutations in GJB2, encodingconnexin 26, as well as the frequency of the gene makes this genethe most common cause of HL in Middle East. The allele frequencyof c.35delG ranged from 5% to 53% in different cities of Turkey [82].This frequency was from 38% to almost 0% in different part of Iran[40,100]. In Pakistan the frequency of GJB2 (DFNB1) mutations isabout 6.1% [101], of which W77X and W24X were the mostprevalent mutations with a homozygote frequency 0.006 [101].Moreover, the W24X mutation is also the most prevalentmutation in India with a frequency 0.17 for homozygotemutations [102]. For Israel and Palestine the c.35delG andc.167delT mutations were the most prevalent with a frequencyof 0.39 homozygous or compound heterozygous [103,104]. Thisrate for Lebanon, Jordan and Iran is about 0.11–0.33 for the mostprevalent mutation c.35delG in these countries [104,105]. Otherrelatively common deafness genes include SLC26A4, MYO15A,TECTA, OTOF, and TMC1. In Turkey, the relatively common deafnessgenes following GJB2 are MYO15A, TMC1, TMIE, and OTOF with afrequency of 62%, 9.9%, 6.6%, 6.6%, and 5.0%, respectively [106].The GJB2, SLC26A4, and TECTA were the most prevalent genesinvolved in NSHL in Iran with a frequency of 19%, up to 10%, and4%, respectively, followed by MYO15A, ILDR1, TMC1, PJVK, LRTOMT,MYO7A, OTOF, and MARVELD2 [38,107,108]. In addition, mutationsin SLC26A4, GJB2, MYO15A, TMC1, and OTOF were reported with7.2%, 6.1%, 5%, 3.4%, and 2.3% frequencies, respectively, in the deafpopulations from Pakistan [102,109,110] and mutations inMYO15A and TMC1 were found in 7.8% and 3.9%, respectively, offamilies without GJB2 mutations from Tunisia [69,111]. The GJB2

mutations in Jewish Ashkenazi and Palestinian deaf patientsaccount for 70.4% and 11% [112] of total mutations, respectively.Founder effects, heterozygote advantage, and assortative matinghave all been proposed to explain the relatively high frequency ofGJB2 [10,113]. Fig. 1 shows the map of Middle East comprises all ofthe reported genes involved in AR and ADNSHL in countries as wellas the number of mutations identified in each gene. As can be seenin this map the most significant findings are the extreme locus andgene heterogeneity and allelic heterogeneity and differentspectrum of genes and mutations in each country. This reviewarticle lacks the HHL information for 18 Middle Eastern countries,


for which we could not find any publication. In many others wecould only find few papers. Therefore, the need to investigate thegenetic causes of HL is a necessity.

9. Future direction

There is no question that soon or later all the genes contributingto AR as well as AD NSHL will be identified but proper systematicapproach could facilitate these finding and benefit the society. TheDNA bank and complete clinical profile of the families withappropriate consent form should be established in each country. Inthe future, gene discovery and functional genomics in the auditorysystem will continue at a rapid pace. To this end, we are ever closerto an enhanced understanding of the hearing process, which willlead to increased availability of diagnostic and presymptomaticgenetic testing options, early intervention, and disease basedtreatments.

Conflict of interest statement

The authors declare that they do not have a conflict of interest.

Acknowledgements

We particularly wish to thank Ms. Valeh Hadavi, MojganBabanejad, Zohreh Fatahi, as well as Ms. Niloofar Bazazzadegan forassistance with literature reviews, and preparation of this paper.

Appendix A. Supplementary data

Supplementary material related to this article can be found,in the online version, at http://dx.doi.org/10.1016/j.ijporl.2014.08.036.

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Genetics of non-syndromic hearing loss in the Middle East

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