A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone

Christine Dos Santos, Laurent Essioux, Cécile Teinturier, Mäité Tauber, Vincent Goffin & Pierre Bougnères

Nature Genetics, July 2004

Outline

Introduction Growth Hormone Receptor (GHR) Allellic differences in growth rate Relevance of findings

Growth Hormone Therapy

Growth hormone therapy may be necessary for some of the population

Where does normal pathway deviate in response to growth hormone?

Image taken from BioCarta.com

Growth Hormone Pathway

Image taken from BioCarta.com

Growth Hormone Pathway

Problems associated with pathway

•Lack of growth hormone production

•Problems with the growth hormone receptor (GHR)

•Downstream components

GHR and downstream components are obvious choices for study on problems associated with growth hormone sensitivity

Growth Hormone Receptor

Transmembrane proteinCoded for by 9 exons246aa extracellular domain (exons 3-7)Single transmembrane domainSingle cytoplasmic domainDimer formation

Growth Hormone Receptor Variant allele d3-GHR

Isoform lacking exon 3 Exon 3 codes for 22aaConserved in mammalian species

important role in protein function

Possible loss of glycosylation siteDifference in receptor domain due to change in

highly conserved amino acid at end of exon 2Dominant over full length isoform

Isoform Response to GH

Children chosen with normal growth hormone levels

•Short for Gestational Age (SGA) – small birth size

•Idiopathic Short Stature (ISS) – normal birth size, slow growth

Data Collection

•Growth rate monitored for first two years of hormone administration

•Individuals tested for GHR genotype

•Only subjects of European origin used in study

•Response to growth hormone measured

Response to GH

Response to GH

Striking increase in response to GH in children carrying at least one d3-GHR allele

Linear Regression Model

GHR genotype has a significant effect on growth acceleration

•(P<10-6 for first year, P<0.005 for second year)

•Nine other tested polymorphisms had no correlation

Activities of GHR and d3-GHR

Transfected 293 HEK fibroblasts with full length GHR, d3-GHR, or GHR/d3-GHR

LHRE-luciferase assay used Cells exposed to varying GH levels Consistent higher induction of reporter

construct by d3-GHR (~30%)GH levels used were low to ensure in vivo

relevance

Relevance Recent recombinant GH use approved by

FDA and ERA for children Genotyping for a single polymorphism can

be carried out efficiently Personalized dose regimen can reduce

costs and improve treatment success Half of people of European descent are

heterozygous or homozygous for d3-GHR

Conclusion

Individuals with d3-GHR isoform have ~twice the growth rate in response to GH as homozygous GHR subjects

This isoform is present at high levels in the human population (~50%)

Efficient cost effective genotyping can lead to improved treatment regimens for patients

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