Endocrine Abstracts (2004) 7 P137

Frequency of single nucleotide polymorphisms in the GHRH receptor gene in short children

KG Smith1, M Gueorguiev1, EF Adams2, CA Mein1, LB Johnston1, SE Bonner3, P Froguel4, MO Savage1, AB Grossman1 & M Korbonits1


1Department of Endocrinology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK; 2Pharmaceutical Sciences Research Institute, Aston University, Birmingham, UK; 3Department of Breast and Endocrine Surgery, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK; 4Hammersmith Genome Centre, Imperial College, Hammersmith Hospital, London, UK.


A number of single nucleotide polymorphisms (SNPs) have been identified in the GHRH receptor gene. Two of these SNPs, A57T and V225I, have been found to cause an increased cAMP response to GHRH stimulation in vitro, and it has been suggested that they may be associated with the abnormal biochemistry in patients with somatotroph adenomas. The objective of this study was to clarify the frequencies of these SNPs in the normal population and in subjects with short stature. The subjects sampled included 380 normal subjects and 40 children with idiopathic short stature. Samples were genotyped using either primer induced restriction enzyme analysis or 5'-exonuclease assay. A proportion of the findings were confirmed using direct sequencing.

The V225I SNP was not present in any of the 420 samples, while 2/54 and 1/26 heterozygotes have been reported previously in two acromegalic cohorts. The A57T SNP was found in a heterozygous form in 3/40 of the short stature subjects' samples. The height, weight, BMI, maternal and paternal height of these heterozygote children were not significantly different compared to the homozygote wild-type group. The frequency of the A57T SNP (7.5%) observed in our population of children with idiopathic short stature is comparable to that reported earlier for a normal population (3/40, 7.5%) or an acromegalic population (4/54, 7.4%) in one study, but is lower than reported in another study (normals 5/21, 24%; patients with acromegaly 10/41, 25%). In conclusion, the absence of the V225I SNP in 420 germline DNA samples suggests that it is very rare, and may be either a polymorphism that pre-disposes to acromegaly or a somatic mutation that occurs in GH-secreting adenomas. The frequency of the A57T SNP is variable in different populations and further study is needed to clarify its effect on GH regulation. However, it is unlikely to play a significant role in the genetic determination of short stature.

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