Albinism Paper-Genetics perspective
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Transcript of Albinism Paper-Genetics perspective
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Albinism: The prevalence, stigma, and truth.
Shemuel Patton
Nevada State College
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Table of Contents
I. Introduction
II. Discussion
III. Summary
IV. References
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Abstract
Albinism is the loss of melanin production within melanin producing cells, melanocytes. The
loss of melanin synthesis is due to certain mutations of particular genes on particular
chromosomes, the location and type of mutation of the gene determines the form of albinism
expressed. While albinism is a disease observed in several different ethnic populations, the types
of albinism expressed by individuals tend to be ethnically segregated. Research has also found
that the complexity and severity of particular types of albinisms depend upon particular
mutations occurring in conjunction with one another as well the inheritance patterns of the
mutated alleles. For oculocutaneous albinism type two (OCA2), the most prevalent and highly
mutated forms of albinism, becomes more severe when the "traditional" OCA2 gene is paired up
with another mutation that causes an alternative form of albinism; this is significant because
OCA1 is currently the most severe form of albinism do to the complete lack of pigmentation.
Keywords: Missense, phenotype, hypopigmentation, alleles, melanocytes,
phaeomelanosomes, eumelanosomes, frameshift mutation, truncation, consanguity
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Albinism: The prevalence, stigma, and truth.
Albinism is a congenital disease that is unanimously characterized by poor vision and
variable pigmentation of the physical appearance, phenotype, of an individual (Montoliu, L. et. al
2013). Albinism is found in a variety of species, including but not limited to mice, vegetables,
scorpions, and reptiles; in this paper I will be focusing on albinism found within humans. There
are forms of albinism that are associated with specific mutations, some albinisms are caused by a
direct mutation in the gene responsible for the production of melanin. While there are some
albinisms caused by mutations of proteins, also known as missense mutation; missense mutation
is caused by the alteration of a single base pair nucleotide which alters the amino acid used and
ultimately the function of the resulting protein. Until recently, there was not much known about
albinism on the molecular level and its many forms expressed within species; with the
development of technology, there have been an increase in studies regarding albinism (Montoliu,
L et. al 2013). In fact, prior to the year 2007, scientists only knew of seven genes believed to
result in albinism but researchers are continuing to find that there are in fact several other genes
and proteins associated with albinism. The studies conducted have illuminated the molecular
processes occurring in individuals with albinism and have unearthed new causes (in regards to
mutations within genes and proteins) and ultimately new forms associated with the new causes.
Albinism is not a disease that appears to be solely endemic to a certain group of people, it
is a disease that has been observed and studied in several populations worldwide. However, as I
will discuss later in the paper, the form of albinism depends upon which genes or proteins have
been mutated; the genes associated with particular forms of albinism tend to be specific to
particular areas that people with these alleles reside. It has been observed and documented by
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several researchers, particular forms occur at higher frequencies in certain ethnic groups while
the same form will occur at an abysmally low frequency in another ethnic group.
In this paper, I will discuss the most severe and common forms of albinism found within
populations and their associated genes that cause the specialized expression of albinism. While I
will not be covering albinism in the entirety of its forms due to the varying amounts of genes
responsible for the known eighteen forms of albinism, I would like to inform you that albinism
occurs in several forms and is the result of several mutations of genes on varying chromosomes.
I will also discuss the diseases and conditions people with albinism are more susceptible and
prone to acquire due to a severe lack of melanin producing cells, melanocytes. I will also briefly
elaborate on the social strata people with albinism experience within their societies in different
regions of the world. By the end of this paper, you will be informed about the genes that result in
varying forms of the most frequent types of albinism, the limited amount of treatments and
protective care for those with albinism, as well as the manner in which albinos are treated within
African societies.
Albinism-Society
Due to recent media coverage about the maltreatment experienced by albinos in
Tanzania, I decided to research where the acts of violence against albinos stem from in sub-
Sahara Africa.In sub-Saharan Africa people with albinism are said to be the result of witchcraft
due to someone within the family committing a wrongdoing against someone, which than placed
a curse of paleness upon resulting offspring. In Nigeria there is a city called Koho, and in Koho
the tribes believe that albinos are spirits, folklore states that albinos are unable to die a natural
death like humans and instead disappear like dust in the wind (Blankenberg, N. 2000).Similar to
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other societies in under-developed regions, people within Koho society believe the mother is
solely at fault for producing an albino child; having an albino child within this society would not
only result in the mistreatment of the child but also the mother ( Lund, P. 2002).
In Zulu culture, one of the largest ethnic groups in South Africa, it is believed that
taunting or teasing of an albino person will result in an albino producing curse within their
family lineage. This fear and misunderstanding leads to the avoidance and ultimate isolation for
albino people, commonly referred to as Isishawa (the cursed), in Zulu culture (Blankenberg, N.
2000) .Reversely, in Soweto south Africa, albinos are treated kindly and with reverence because
the people attribute the paleness of skin to a direct connection to the spirit world. In Soweto
culture, giving birth or being born an albino increases one's social status significantly
(Blankenberg, N. 2000).
The purpose of this paper is to provide a scientific based explanation of albinism in light
of social stereotypes and stigmas. The most recently publicized being the increased mistreatment
of albinos in Tanzania, this mistreatment has been addressed by several local government
officials, UNICEF, and foreign governments that provide Tanzania financial assistance. The
reasons behind the mistreatment is due to the common, and often fatal, belief that albinos have
special "magical powers" and their organs contain these "powers" as well. Due to this
misconception , hair, internal organs, skin, and limbs are harvested to be used as talisman to
make people richer, more powerful, and prosperous in life (Cimpric, A. 2010). The Tanzanian
government in conjunction with UNICEF have embarked on a campaign to not only educate
Tanzanians but to also enhance the safety of albino individuals.
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Albinism-Molecular level.
Albinism is a congenital disease that occurs world-wide with a frequency of 1/20,000
individuals ( Gargiulo, A et al 2011). It is characterized by poor vision and variable
hypopigmentation; people with albinism have a deficiency in the melanin pigment biosynthesis-
this reduction of melanin biosynthesis in melanocytes results in decreased amount of
pigmentation (Oetting 1996).The first form of albinism to be discussed is the severest known
type, oculocutaneous albinism; which effects the pigmentation of the skin, hair, and eyes. This
type is not similar to ocular albinism, which only effects the pigmentation of the eyes. Prior to
2007, it was believed that four genes and protein mutations caused oculocutaneous albinism in
humans, but with advancements of technology scientist have discovered that there are currently
seven known genes and protein mutations that cause oculocutaneous albinism (OCA); the
amount of gene and protein mutations appear to be expanding with the increase of research
focused on albinism. With the discovery of new genes, new forms of albinism are classified; this
increase of classification displays how diverse the disease is and the many forms it can be
expressed due to polymorphisms in genetic populations.
The first form of OCA is OCA1, OCA1 is caused by a frameshift mutation of the
tyrosinase gene (TYR).This gene mutation was first observed in a Japanese man and was also the
first mutation to be identified as causing albinism within humans; however OCA 1 is more
prevalent in European and Asian populations (Yuasa, I et al 2007). The frameshift mutation
suppresses enzymatic activity in the melanin biosynthesis pathway, the amount of melanocytes
may be unaffected but the ability to produce melanin in the melanocytes is affected by the TYR
gene mutation. Individuals with OCA1 are more susceptible to sunburns and skin cancers.
OCA1 can be characterized into two individual sub groups, the first being OCA1A; individuals
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with OCA1A suffer from complete hypopigmentation, no melanin is able to be produced within
the melanocytes. Individuals with OCA1A lack pigmentation in their skin, hair, and eyes; the
lack of pigment in the eyes results in poor visual acuity.The second form of OCA1, is OCA1B
which is also caused by the mutation of the TYR gene but the mutation does not suppress
enzyme activity entirely and a minimal amount of melanin is able to be produced. Individuals
with this form of albinism are still characterized by pale skin, hair, and eyes but they have more
pigmentation in their eyes and hair than individuals with OCA1A (Manga, P et. al 2013). The
TYR gene is located on the eleventh chromosome and is one of two causes that hinder the
enzymatic production of melanin, the other cause is the tyrosinase related protein-1 (TYRP)
mutation located on the ninth chromosome.
The third form known as OCA3 (also referred to as rufous OCA) is caused by the
mutation of TYRP1; caused by the truncation of two exons found in the TYRP1 protein. The
truncation of these exons produce premature stop codons that produces a nonsense mutation; the
result if this nonsense mutation is the partial development of melanin. This form of albinism is
more frequent among south African populations and practically non-existent within Caucasian
populations; the allele frequency of this mutation is 1 in 8580 (Study of OCA and
vitiligo).Individuals with this form of albinism tend to develop pigmentation throughout their
lifetime and appear to have less ocular problems; researchers were able to study the melanocytes
of individuals with OCA3 and found that their melanocytes contain mature eumelanosomes and
premature phaeomelanosomes depending upon the stage of melanin production .The increase in
melanin (although slight) allows the retinal visual cells to develop properly because the synthesis
of melanin in the retinal pigment epithelium (RPE) is able to occur during development; in
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OCA1 and OCA2, the absence or decrease of melanin altered the development of the visual cells
which results in poor vision(Manga, P. et. Al 2013)
The second form of OCA, OCA2 is the most prevalent form worldwide and within
African populations; within African populations OCA2 occurs at a frequency of 1/3900. OCA2
is caused by a mutation in the OCA2 gene, previously referred to as the P gene; OCA2 is located
on the fifteenth chromosome and is caused by a deletion in exon number seven but research has
found that transgenic deletions of exons 3-20 produce OCA2 as well (Ibarrola-Villava et. al
2010).The most common exon, seven, deleted codes for the ionic transport protein that is
responsible for the pH regulation of melanosomes (Oetting 1996). Recently researchers have
been studying the other frameshift, nonsense, and missense mutations that have been found to
produce OCA2; unfortunately due to recent discovery not much is known about the function of
the deleted exons but it is believed that they are responsible for the production transmembrane
proteins. Similar to OCA1,OCA2 can be separated into two subgroups: the first subgroup being
OCA2 which is characterized by hypopigmentation of varying degree, yellow to brown hair, pale
skin, and light colored eyes. The second subgroup is OCA2B, also known as brown albinism, is
characterized by light brown skin, beige to brown colored skin, and blue-green to brown colored
irises. Individuals with OCA2 and OCA2B produce pigmentation through their lifetime but are
still susceptible to sunburn, blistering, and freckling associated with sun exposure.
The fourth form, and one of the rarest forms worldwide is OCA4; OCA 4 is prevalent in
within Japanese populations. The mutation in the membrane-associated transporter protein gene
(MATP also referred to as the SLC45A2) caused by SNPs in one of the seven exons of the
MATP gene causes form OCA4. While researchers are unsure what role the MATP gene plays in
melanin synthesis, they believe one of the proteins produced in this gene is responsible for the
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transportation of proteins necessary for melanin synthesis. The MATP gene was first discovered
in a Turkish man and has since been identified in German, Korean, and Japanese patients,
Researchers attribute the rareness of OCA4 is due to a founder chromosome found in a common
ancestor of Caucasians and Asian populations that occurred 15,000-35,000 years ago (Yuasa, I
et. al 2007).
The last three forms of OCA I will be discussing are the most recently discovered and
therefore the functions of genes are relatively unknown. OCA5 was discovered in a Pakistani
family and this form of albinism had a high occurrence of consanguity, consanguity in albinism
is not uncommon but the high occurrence of inheritability of the alleles was a novel discovery.
The gene, located on the fourth chromosome, that causes this form of albinism is unknown due
to the fact that this new form was discovered in 2012 and appears to occur in conjunction with
other forms of OCA. OCA6, discovered in 2013, was discovered in Chinese patients who
appeared to have autosomal recessive OCA but with varying degrees of hypopigmentation; this
form of albinism is characterized by light hair that darkens over time and iris transillumination
(Grønskov, K. et. al 2013). With further research, researchers found that this form of albinism is
the rarest form of OCA due to the low frequency of these recessive alleles in most populations.
The gene responsible for the expression of albinism is the SLC24A5, located on the fifteenth
chromosome, experiences a frameshift mutation and nonsense mutation that produces an amino
acid at a position that promotes the suppression of melanin biosynthesis The amino acids reduce
the number and size of melanocytes produced while also hindering the maturation of
melanocytes. Researchers also found that OCA6 can be caused by a deficiency in the production
of Hermansky-Pudlak syndrome protein altered the production of protein complexes that
ultimately interrupt the non-mutated SLC24A5 gene from producing melanosomes and the
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biosynthesis of melanin; Hermansky-Pudlak syndrome is a form of syndromic albinism that can
be caused by several mutations on several chromosomes.
The last form OCA7, was discovered in 2013 and was first observed in a Denmark family
that was homozygous for the mutation. . Individuals with OCA7 had transillumination of the
irises (lack of pigment which makes the irises appear clear), reduced visual acuity,
nystagmus( rapid involuntary movements of the eyes), and chiasm misrouting of their optical
tracts (Gronskov et. al, 2013 ).OCA7 is caused by an nonsense mutation of the C10orf11 gene
located on the tenth chromosome,OCA7 is characterized by lighter pigmentation of the skin
(compared to unaffected relatives) and severe ocular problems. C10orf11 encodes for 198 amino
acid protein containing three leucine-rich repeats(LRRs) and one leucine-rich repeat C-terminal
domain(LRRCT), the LRRs and LRCT are responsible for the signaling and adhesion of
extracellular matrix assembly, neuronal development, and RNA processing of melanocytes
( Grønskov, K. et. Al 2013).
Problems and Treatments.
The common trait that characterizes albinism is visual problems in individuals;
individuals with albinism suffer varying forms of visual problems due to the decreased amount
of melanin that is required to form proper retinal pigmentation and photoreceptors (rods and
cones). This decrease in pigmentation results in foveal hypoplasia which is the
underdevelopment of the eye's internal surface, responsible for seeing detail.Individuals also tend
to have a reduced amount of retinal ganglion cells, a type of neuron, that are photoreceptors that
receive and decipher visual information received; in conjunction with increased sensitivity to
light and foveal hypolasia, individuals experience a very low visual acuity. Individuals with
albinism, mainly those with OCA, suffer from strabismus which is the misalignment of the eyes
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and photophobia(a sensitivity to light); the misalignment can be corrected with surgery but the
surgery rarely improves the visual acuity of the individual ( Tavakolizadeh, S et. Al 2011).
Individuals with albinism also have a higher susceptibility to skin cancers due to
hypopigmentation, while individuals are prone to blistering, freckling, and melanoma; melanoma
is the most dangerous form of skin cancer that is a result of UV damage to skin cells and
produces cancerous tumors. Since OCA has prevalence of 1 in 1000 in sub-Saharan Africa,
researchers have been discovering ways to protect individuals from skin cancers and provide
health information to affected individuals and their families. Researchers and health workers
suggest those with OCA wear photo-protective clothing, such as hats with wide brims, long
sleeve garments, protective eyewear, and broad spectrum sunscreen; the implementation of such
measures in sub-Saharan Africa need to be proposed by physicians because these measures are
not needed by the majority of the population and are therefore viewed with minimal regard
(Photochemistry and albinism). Researchers and health workers also suggest that individuals
with OCA utilize natural shade but also created shade, either from umbrellas or structures built to
protect children and individuals from excessive sun exposure; unfortunately such structures are
not frequent in southern Africa but the frequency of them would potentially protect several OCA
individuals from excessive sun damage.
Lastly, there are not many treatments available or discovered for individuals who suffer
from hypopigmentation, the main reason being there are several causes and mutations that cause
the phenotypic expression of albinism. The increase of mutations makes treating albinism as one
disease difficult because many factors are involved and can not be remedied the same as a
different factor. However, scientists believe that tracking the mutations and understanding the
role the mutated gene plays in the production of melanin will allow for effective treatments to be
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created and implemented; meaning if a patient is known to express albinism due to a mutation of
one gene, such as tyrosinase (TYR), the patient can undergo treatments that facilitate the increase
of TYR activity in melanocytes. Creating effective treatments for less variable types of albinism
will be easier to produce but will prove difficult for the more variable types of albinism, but gene
therapy for individuals with albinism becomes more likely with continued research and studies.
Conclusion.
Despite the fact that I focused on the most prevalent and severe non-syndromic forms of
albinism, I again wish to reiterate that there are currently a total of eighteen different forms of
albinism. Seven of which I discussed throughout this paper and the other ten forms tend to be
less prevalent within populations but also have a larger variety of gene mutations contributing
and causing these particular syndromic forms of albinism. The eighteenth form is ocular
albinism, and tends to be more frequent within males because it is an X-linked disease; while the
syndromic albinisms and ocular albinism are important forms of the disease the molecular
processes of this diseases were beyond the scope of this paper due to the sheer complexity of the
biosynthesis and underlying factors. Understanding the biosynthesis and roles of the genes that
cause oculocutaneous albinism allows researchers to better understand the syndromic forms of
albinism and use the discovered information as a template for exploring the syndromic forms.
Albinism is a complex disease that effects all ethnicities to varying degrees based upon
inherited forms from parents or forms caused by mutations during development. There are
several genes responsible for the expression of albinism and several mutations can occur within
one gene to produce a variant form of a type of albinism, this variation in mutations prevents
diagnostic screening from being as effective as it is in other diseases where there are not several
variables. Diagnostic screening and treatments are possible for "simple" forms of albinism that
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possess expected gene mutations, although scientists are discovering that the "simple" forms of
albinism are not as simple as previously assumed. With the increase of polymorphisms in alleles
and the sharing of once isolated alleles are giving rise to more complex forms of albinism;
despite this challenge, several researchers continue to dedicate their career to unraveling the
mystery behind albinism and hopefully provide forms of treatments for those with the disease.
Until treatments are available, those with albinism should wear longer garments to protect their
skin from ultraviolet radiation that could result in skin cancer, lesions, blistering, and freckling.
The necessity to regularly apply broad spectrum sunscreen and wear protective eyewear and
garments should be addressed by doctors, especially within societies where such preventative
measures normally do not need to be taken. Addressing these needs would not only increase the
overall health of an albino individual but would also reduce the stigma associated with having
fairer skin; providing accurate and scientific reason behind this disease would educate those with
albinism as well as those who are misinformed about albinism.
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