Activating and inactivating mutations in the human GNAS1 gene

GNAS1 on chromosome 20 is a complex locus, encoding multiple proteins, of w hich G(s)alpha, the alpha-subunit of the heterotrimeric stimulatory G prote in G(s), is of particular interest clinically. Amino acid substitutions at two specific codons lead to constitutive activation of G(s)alpha. Such gain -of-function mutations are found in a variety of sporadic endocrine tumors and in McCune-Albright syndrome, a sporadic condition characterized by mult iple endocrine abnormalities. Heterozygous loss of G(s)alpha function resul ts in the dominantly inherited condition, Albright hereditary osteodystroph y (AHO). Here we present a review of published GNAS1 mutations and report 1 9 additional mutations, of which 15 are novel. A diverse range of inactivat ing mutations has been detected, scattered throughout the gene but showing some evidence of clustering. Only one, a recurring 4 bp deletion in exon 7, could be considered common among AHO patients. The parental origin of the mutation apparently determines whether or not the patient shows endorgan re sistance to hormones such as parathyroid hormone. G(s)alpha is biallelicall y expressed in all tissues studied to date and thus there is no direct evid ence that this transcript is imprinted. However, the recent identification of other imprinted transcripts encoded by GNAS1 and overlapping G(s)alpha, together with at least one imprinted antisense transcript, raises intriguin g questions about how the primary effect of mutations in GNAS1 might be mod ulated. Hum Mutat 16:183-189, 2000. (C) 2000 Wiley-Liss, Inc.