A study of genetic heterogeneity in Albright hereditary osteodystrophy.

Albright hereditary osteodystrophy (AHO) is a disorder characterised by short stature, obesity, subcutaneous calcifications, brachydactyly and mental retardation. AHO can occur with or without resistance to hormones acting via adenylyl cyclase, even within one kindred. Both phenotypic forms can result from identical heterozygous deactivating mutations in the gene encoding Gsa (GNAS1) leading to reduced Gsa acitivity. Parental origin of the mutation is suggested to play a role in the development of hormone resistance. In this study, 27 GNAS1 mutations have been identified, of which 25 were unique, in a cohort of 58 individuals with characteristics of AHO. The mutations were localised throughout the gene although 7/27 (26%) were present in exon 1. All mutations were predicted to lead either to amino acid substitutions in functionally or structurally important domains or to truncated proteins. Parental origin of the mutations was established in 17 parent-to-child transmissions (14/17 maternal and 3/17 paternal transmissions) and supports a parental effect as mutations on the maternally derived allele always resulted in offspring with AHO and hormone resistance and mutations on the paternally derived allele in offspring with AHO and hormone responsiveness. Tissue specific imprinting of GNAS1 has been excluded as the mechanisms leading to the observed parental effect. Furthermore, a second locus for AHO on chromosome 2q37 has been identified by deletion mapping. The data did not reveal if AHO localised to this region of the genome results from a single gene defect or from a deletion of contiguous genes. Linkage of the gene for brachydactyly E, one of the typical characteristics of AHO, to 2q37 was excluded in one extensive kindred with isolated autosomal dominant brachydactyly type E.