Molecular Genetics of Growth Hormone Primus E Mullis KIGS 10 Year Book, 1999.
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Transcript of Molecular Genetics of Growth Hormone Primus E Mullis KIGS 10 Year Book, 1999.
Molecular Genetics of Growth Hormone
Primus E Mullis
KIGS 10 Year Book, 1999
Hypothalamus
Pituitary GlandGas proteinAdenyl cyclaseProp-1BtkPit-1
LiverJak2Stats
BloodIGFBPsIGFBP proteases
Bones
GHRHSomastatin
GHRH receptor
GH receptor
IGF-I -receptor
Schematic representation of the hypothalamic-pituitary-peripheral tissue axis
P E Mullis - KIGS 10 Year Book, 1999
P E Mullis - KIGS 10 Year Book, 1999
Gene Disorder in rodents Disorder in humans Inheritance
GHRH Not identified Not identified Not identifiedGHRH receptor Little/little mouse Isolated GHD, type IB Autosomal recessiveGH Dwarf rat Isolated GHD, type IA,
IB, IIAutosomal recessive,autosomal dominant
Bruton´s thymidinekinase
Not identified Isolated GHD, type III x-linked
GH receptor (chicken) Laron syndrome Autosomal recessive,autosomal dominantX-linked
IGF-I Identified GH resistance Autosomal recessiveIGF-II Not identified Not identified Not knownIGH receptors Not identified Not identified Not knownIGFBPs Not identified Not identified Not knownIGFBP proteases Not identified Not identified Not knownPit-1 Snell mouse GH/TSH/PRL deficiency Autosomal recessive,
autosomal dominantProp-1 Ames mouse GH/TSH/PRL/LH/FSH
deficiencyAutosomal recessive
GHRH, growth hormone-releasing hormone; GHD, growth hormone deficiency; GH, growth hormone;IGF, insulin-like growth factor; IGFBP, insulin-like growth factor-binding protein; TSH, thyroid-stimulating hormone; PRL, prolactin; LH, luteinising hormone; FSH, follicle-stimulating hormone
Phenotype and genetic disorders of GH biosynthesis and action
Familial isolated GHD; patterns of inheritance
P E Mullis - KIGS 10 Year Book, 1999
Category Inheritance GH radioimmuno-assay
Candidate gene Status
Type IA Recessive Absent hGH-1 Deletions/mutationsFrameshift(Signal peptide)
Type IB Recessive Absent/low hGH-1
GHRHGHRH receptorTrans-acting factorsCis-acting elements
Splice site mutationsStop codonFrameshiftUnlikelyMutationsMutations/deletionsMutations/deletions
Type II Dominant Low hGH-1 Splice site mutations
Type III X-linked Low Unknown
P E Mullis - KIGS 10 Year Book, 1999
Missense mutation
1 1 2 3 4 5’exons
3 18 56 57 56 57ACA-->ACG CTG C->TGC GAG TCT AT--> GCT TATThr Ala Leu Cys Glu Ser Val Tyr
20TGG-->TAGTrp Stop
GT GAGT --> GTGAGCGT-->AT+28G->AGT--> CTGT--> TT
x
Frameshift
Stop oodon
Splicing error
Silent mutation
I II III IV VX
23 33GAG-->TAG GAA-->GGA GU Stop Glu Gly GTC-->GTG
Val Val
183GGC--> CACArg His
173
3’
Schematic representation of the GH-I gene showing the locations of various mutations