A new mutation in the growth hormone-releasing hormone receptor gene in two Israeli Arab families.
BACKGROUND
Mutations in the GHRH receptor gene (GHRH-R) are emerging as a common cause of familial isolated GH deficiency (IGHD).


METHODS
We searched for GHRH-R mutations in 10 patients with IGHD of Israeli-Arab origin, belonging to two highly consanguineous families.


METHODS
Analysis of the 13 coding exons, the intron-exon boundaries, and the proximal promoter of the GHRH-R was performed by denaturing gradient gel electrophoresis. Abnormally migrating bands were sequenced. The newly found mutation was inserted into GHRH-R cDNA. Wild type and mutant receptor were expressed in Chinese hamster ovary (CHO) cells, and the cAMP response to GHRH was measured.


RESULTS
All patients were homozygous for a novel GHRH-R missense mutation in exon 11 that replaces arginine with cysteine (R357C). Functional assay demonstrated complete inactivity of the mutant receptor in vitro. The prevalence of the mutant allele in the Israeli-Arab population was found to be 2%. All the patients had low but detectable GH reserve, proportionate short stature, and growth retardation since early childhood, with good growth response to GH treatment. Magnetic resonance imaging, performed in 3 patients, revealed a normal sized anterior pituitary in one patient evaluated at early childhood, and a borderline hypoplastic gland in the 2 patients evaluated at puberty.


CONCLUSIONS
We describe a novel missense mutation in the GHRH-R. The high incidence of the mutant allele in Israeli Arabs suggests that the mutation may be a common cause of familial IGHD in this population.
Haskin
O
O
Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes Petach Tikva, Israel.
Lazar
L
L
Jaber
L
L
Salvatori
R
R
Alba
M
M
Kornreich
L
L
Phillip
M
M
Gat-Yablonski
G
G
D000293:Adolescent; D000328:Adult; D000818:Animals; D018912:Arabs / Q000208:ethnology / Q000235:genetics; D016466:CHO Cells; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000172:deficiency*; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010903:Pituitary Gland, Anterior; D015995:Prevalence; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D014162:Transfection
D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor