GNAS Spectrum of Disorders

Abstract

The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitous signaling protein mediating the actions of many hormones, neurotransmitters, and paracrine/aurocrine factors via generation of the second messenger cAMP. GNAS gives rise to other gene products, most of which exhibit exclusively monoallelic expression. In contrast, Gsα is expressed biallelically in most tissues; however, paternal Gsα expression is silenced in a small number of tissues through as-yet-poorly understood mechanisms that involve differential methylation within GNAS. Gsα-coding GNAS mutations that lead to diminished Gsα expression and/or function result in Albright’s hereditary osteodystrophy (AHO) with or without hormone resistance, i.e. pseudohypoparathyroidism type Ia/Ic and pseudo-pseudohypoparathryodism, respectively. Microdeletions that alter GNAS methylation and, thereby, diminish Gsα expression in tissues in which the paternal Gsα allele is normally silenced also cause hormone resistance, which occurs typically in the absence of AHO, a disorder termed pseudohypoparathyroidism type-Ib. Mutations of GNAS that cause constitutive Gsα signaling are found in patients with McCune-Albright syndrome, fibrous dysplasia of bone, and different endocrine and non-endocrine tumors. Clinical features of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.

Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes

“…Loss of function of GNAS (also known as Guanine Nucleotide Binding Protein (G Protein), Alpha Stimulating Activity Polypeptide 1) on the maternal allele is known to cause basal ganglia calcification though this is not considered as PFBC. GNAS is a complex imprinted locus that produces multiple transcripts through alternative splicing and promoters [26]. GNAS mutations can result in a group of pseudohypoparathyroid disorders which include pseudohypoparathyroidism type Ia, pseudohypoparathyroidism type Ic, pseudopseudohypoparathyroidism and McCune-Albright syndrome.…”

Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives

“…The GNAS locus is a complex, imprinted gene that uses several promoters to produce assorted gene products, including the ubiquitously expressed α-subunit of the G s stimulatory protein (G s α) [2]. The primary role of G s α is to couple hormones and certain seven-transmembrane receptors to adenylyl cyclase, facilitating production of intracellular cyclic AMP [3]. G s α is comprised in part by an intrinsic GTPase domain, which binds guanine nucleotide and interacts with specific receptors and effectors.…”

Pseudohipoparatiroidismo de presentación tardía: reporte de dos casos

“…Como mencionamos previamente, dado que GNAS se expresa de forma bialélica en la mayoría de los tejidos, (ej, hueso condrocitos y placa de crecimiento), se postula que en la OHA las características clínicas se producen por haploinsuficiencia (funcionamiento de solo un alelo) del GNAS en estos tejidos. La talla baja y la braquidactilia de la OHA pueden deberse a la fusión prematura de la epífisis en huesos largos y tubulares, lo que demuestra la necesidad de dos copias funcionales del GNAS para el crecimiento y maduración normal del cartílago de crecimiento 5 .…”

“…La unión de estas hormonas a su receptor lleva a la activación de la adenilciclasa con el consecuente aumento del AMPc 4 . Mutaciones del GNAS generan disminución de la expresión y/o función de la Gsa lo que se manifiesta clínicamente como OHA con o sin resistencia hormonal 5 . En Chile, a nuestro mejor entender, se han publicado sólo 2 casos de PHP 6,7 , correspondiendo uno de ellos a la forma clásica de presentación en la infancia 6 .…”