Transcript Dos Santos, 2004

A common polymorphism of the
growth hormone receptor is
associated with increased
responsiveness to growth hormone
Nature Genetics, July 2004
Christine Dos Santos, Laurent Essioux, Cécile Teinturier,
Mäité Tauber, Vincent Goffin & Pierre Bougnères
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?
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
Image taken from BioCarta.com
GHR and downstream components
are obvious choices for study on
problems associated with growth
hormone sensitivity
Growth Hormone Receptor

Transmembrane protein
 Coded
for by 9 exons
 246aa extracellular domain (exons 3-7)
 Single transmembrane domain
 Single cytoplasmic domain
 Dimer formation
Growth Hormone Receptor

Variant allele d3-GHR
 Isoform
lacking exon 3
 Exon 3 codes for 22aa
 Conserved in mammalian species

important role in protein function
 Possible
loss of glycosylation site
 Difference in receptor domain due to change in
highly conserved amino acid at end of exon 2
 Dominant 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 d3GHR 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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