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). Design: 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.
En]KeywordsIGHD GHRH receptor mutation
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- 1.Cogan JD, Phillips JA. Molecular defects in the growth hormone axis. In: Handwerger S ed. Molecular and cellular pediatric endocrinology. Totowa, New Jersey: Humana Press Inc. 1998, 23–38.Google Scholar
- 2.Sizonenko PC, Clayton PE, Cohen P, Hintz RL, Tanaka T, Laron Z. Diagnosis and management of growth hormone deficiency in childhood and adolescence. Part 1: Diagnosis of growth hormone deficiency. Growth Horm IGF Res 2001, 11: 137–65.Google Scholar
- 9.Hofman PL, Pescovitz OH. Growth hormone releasing hormone. In: Handwerger S ed. Molecular and cellular pediatric endocrinology. Totowa, New Jersey: Humana Press Inc. 1998, 85–112.Google Scholar
- 23.Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Advance Data 2000, 8: 1–27.Google Scholar
- 24.Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in girls. Arch Dis Child 1969, 44: 91 -103.Google Scholar
- 27.Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist, 2nd ed. Stanford, CA: Stanford University Press 1959.Google Scholar
- 30.Laron Z, Mannheimer S. Measurements of human growth hormone. Description of the method and its clinical applications. Isr J Med Sci 1966, 2: 115–9.Google Scholar
- 33.Laron Z, Pertzelan A, Karp M, Kowadlo-Silbergeld A, Daughaday WH. Administration of growth hormone to patients with familial dwarfism with high plasma immunoreactive growth hormone. Measurements of sulfation factor, metabolic and linear growth responses. J Clin Endocrinol Metab 1971, 33: 332–42.Google Scholar
- 38.Myers RM, Fischer SG, Lerman LS, Maniatis T. Nearly all single base substitution in DNA fragments joined to a GC clamp can be detected by denaturating gradient gel electrophoresis. Nucleic Acids Res 1985, 1 3: 31 31 -45.Google Scholar
- 41.Levine MA, Eil C, Downs RW Jr, Spiegel AM. Deficient guainine nucleotide regulatory unit activity in cultured fibroblast membranes from patients with pseudohypoparathyroidism type I. A cause of impaired synthesis of 3′,5′-cyclic AMP by intact and broken cells. J Clin Invest 1983, 72: 316–24.Google Scholar
- 51.Connor EE, Ashwell MS, Dahl GE. Sequencing and expression of bovine pituitary growth hormone releasing hormone receptor DNA. 1999 Genebank Accession n. AF184896.1.Google Scholar
- 52.Cardoso JCR, Power DM, Elgar G, Clarck M. Genomic characterisation of putative growth hormone releasing hormone (GHRH) receptor genes in the teleost fish fugu rubripes. DNA Sequence 2003, 14: 1 29–33.Google Scholar