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