RESUMO
OBJECTIVE: Albright hereditary osteodystrophy (AHO) and Pseudohypoparathyroidism type Ia (PHPIa) are caused by an inherited deficiency of Gsalpha, encoded by the GNAS gene. Apart from an exclusive first exon, Gsalpha shares part of the transcribed regions with NESP55, Exon A/B and XLalphas, whose gene products utilize alternative promoter regions of this complex gene locus. However, it is not known, whether the deficiency of all gene products contributes to the AHO and PHPIa phenotype or if they are even causative for some specific symptoms. In these cases, mutations affecting selectively GNAS exon 1, coding only for Gsalpha, would lead to a different phenotype than mutations affecting the common exons 2-13. METHODS: Clinical and molecular genetic analysis of a patient with features of AHO and review of exclusive exon 1 mutations of GNAS. RESULTS: We detected a novel heterozygous 1 bp deletion of a guanine in codon 31 in exon 1 of the GNAS gene leading to a frame shift and premature termination of Gsalpha. The female patient demonstrated a fully expressed AHO and PHPIa phenotype and a decreased Gsalpha protein activity of 62% compared to the wild type. Mutations in exon 1 are almost exclusively disruptive and lead to an AHO phenotype that does not show obvious differences from those provoked by missense or nonsense mutations in exon 2-13. CONCLUSION: Disruptive mutations in exon 1 indicate that exclusive deficiency of Gsalpha is sufficient for the expression of an AHO phenotype, which cannot be compensated by alternative products of GNAS.
Assuntos
Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/genética , Criança , Cromograninas , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/genética , Mutação , Regiões Promotoras GenéticasRESUMO
The parental origin of the additional sex chromosomes in 8 cases with high-order sex chromosome polysomies was determined using DNA polymorphisms. The additional sex chromosomes were paternally derived in 3 48,XXYY cases, and maternal in origin in 1 48,XXXY case and 4 49,XXXXY cases. Thus, all extra chromosomes, within a particular patient, were always derived from only one parent. Their most likely origin was successive nondisjunction at the first and second meiotic division in one germ cell. The mechanism involved remains unclear, but appears to be independent of parental ages.