Identification of two novel deletion mutations within the G(s)alpha gene (GNAS1) in albright hereditary osteodystrophy

Albright hereditary osteodystrophy (AHO) is a genetic disorder characterize d by short stature, skeletal defects, and obesity. Within AHO kindreds, som e affected family members have only the somatic features of AHO [pseudopseu dohypoparathyroidism (PPHP)I, whereas others have these features in associa tion with resistance to multiple hormones that stimulate adenylyl cyclase w ithin their target tissues [pseudohypoparathyroidism type Ia (PHP Ia)]. Aff ected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of G(s)alpha, the alpha-subunit of the G pro tein that couples receptors to adenylyl cyclase stimulation, and in a numbe r of cases heterozygous loss of function mutations within the G(s)alpha gen e (GNAS1) have been identified. Using PCR with the attachment of a high mel ting domain (GC-clamp) and temperature gradient gel. electrophoresis, two n ovel heterozygous frameshift mutations within GNAS1 were found in two AHO k indreds. In one kindred all affected members (both PHP Ia and PPHP) had a h eterozygous 2-bp deletion in exon 8, whereas in the second kindred a hetero zygous 2-bp deletion in exon 4 was identified in all affected members exami ned. In both cases the frameshift encoded a premature termination codon sev eral codons downstream of the deletion. In the latter kindred affected memb ers were previously shown to have decreased levels of GNAS1 messenger ribon ucleic acid expression. These results further underscore the genetic hetero geneity of AHO and provides further evidence that PHP Ia and PPHP are two c linical presentations of a common genetic defect. Serial measurements of th yroid function in members of kindred 1 indicate that TSH resistance progres ses with age and becomes more evident after the first year of life.