EXCLUSION OF THE GHRH GENE AS A CANDIDATE FOR MOST CASES OF FAMILIAL ISOLATED GROWTH HORMONE DEFICIENCY

Abstract

Familial isolated growth hormone deficiency (IGHD) can have autosomal recessive (type I), autosomal dominant (type II) or X-linked (type III) modes of inheritance. White some cases of IGHD are due to deletions or point mutations affecting the growth hormone (GH-1) gene, linkage studies have excluded the GH-1 gene as the locus responsible for a significant proportion of IGHD cases. This fact, along with the positive response in GH secretion after exogenous GH releasing-hormone (GHRH) administration in several affected subjects, suggests that the GHRH gene is a good candidate for some autosomal cases of IGHD. In order in determine the proportion of IGHD cases that may be due to GHRH gene mutations, we studied three highly polymorphic microsatellites (CA repeats) previously mapped close to GHRH on chromosome 20 by linkage. Using these microsatellites as markers for the GHRH locus, we have carried out linkage analysis in 20 unrelated IGHD families (9 type 1, and 11 type II). All available family members were genotyped for the marker D20S44 (no recombination with GHRH at a LOD score of 3.6). Noninformative families were also genotyped for other microsatellite polymorphisms. D20S45 and D20S54 (located at 1 and 2 cM from GHRH, respectively). The segregation pattern of alleles at each of the three loci was compared with that of the disease phenotype. We found at least one recombinant meiosis with discordance between phenotype and genotype in 19/20 (95%) of the families: one family with IGHD II was not informative with any of the markers. Our results were consistent with exclusion of linkage between the GHRH and IGHD loci in all 19 families that were informative. There is a minimal probability (1-2%) of a false negative result due to recombination between the marker and the GHRH gene in each of the 7 families that were not informative with D20S44. Our data indicate that most mutations responsible for IGHD are not within or near the structural gene for GHRH on chromosome 20. Since linkage to GH-I had also been previously excluded in 40% of these families, mutations in other loci different from GH and GHRH must be the cause of IGHD in these patients.