Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor.
BACKGROUND
Both GH releasing- and orexigenic properties of the gut-to-brain hormone ghrelin are mediated by the GH secretagogue receptor (GHSR). Recently in several patients, a missense mutation (p.A204E) resulting in a complete loss of GHSR constitutive activity has been implicated in short stature with dominant transmission.


OBJECTIVE
The objective of the study was to describe the phenotype associated with partial isolated GH deficiency of a young patient born to unrelated parents and identify the molecular basis of his disease.


RESULTS
The growth delay (-3.0 sd) was associated with recurrent episodes of abdominal pain, vomiting, ketosis, hypoglycemia, and a low body mass index. GHSR sequencing revealed that the patient was compound heterozygous for two new defects: 1) an early occurring transition predicting a premature stop codon (c.6G>A, p.W2X) inherited from his unaffected father, therefore strongly arguing against haploinsufficiency as a disease mechanism, and 2) a missense mutation (c.709A>T, p.R237W) inherited from his healthy mother, involving an evolutionary invariant residue from the third intracellular loop. In vitro experiments showed that the p.R237W mutation would result in a partial loss of constitutive activity of the receptor, whereas both its ability to respond to ghrelin and its cell surface expression are preserved.


CONCLUSIONS
These data, which describe the first case of recessive partial isolated GH deficiency due to GHSR mutations and emphasize the physiological importance of the GHSR in somatic growth, are discussed in light of the dominantly expressed p.A204E mutation.
Pantel
Jacques
J
INSERM, U933, 75011 Paris, France. jacques.pantel@vanderbilt.edu
Legendre
Marie
M
Nivot
Sylvie
S
Morisset
Séverine
S
Vie-Luton
Marie-Pierre
MP
le Bouc
Yves
Y
Epelbaum
Jacques
J
Amselem
Serge
S
D001724:Birth Weight; D001827:Body Height; D015992:Body Mass Index; D005260:Female; D005808:Genes, Recessive; D006130:Growth Disorders / Q000235:genetics*; D019382:Human Growth Hormone / Q000172:deficiency*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D009679:Nuclear Family; D010375:Pedigree; D010641:Phenotype; D054440:Receptors, Ghrelin / Q000235:genetics*; D012016:Reference Values; D015183:Restriction Mapping; D035781:Siblings
D054440:Receptors, Ghrelin; D019382:Human Growth Hormone