Activating and inactivating mutations in the human GNAS1 gene

Abstract

GNAS1 on chromosome 20 is a complex locus, encoding multiple proteins, of which Gsα, the α‐subunit of the heterotrimeric stimulatory G protein Gs, is of particular interest clinically. Amino acid substitutions at two specific codons lead to constitutive activation of Gsα. Such gain‐of‐function mutations are found in a variety of sporadic endocrine tumors and in McCune‐Albright syndrome, a sporadic condition characterized by multiple endocrine abnormalities. Heterozygous loss of Gsα function results in the dominantly inherited condition, Albright hereditary osteodystrophy (AHO). Here we present a review of published GNAS1 mutations and report 19 additional mutations, of which 15 are novel. A diverse range of inactivating 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 end‐organ resistance to hormones such as parathyroid hormone. Gsα is biallelically expressed in all tissues studied to date and thus there is no direct evidence that this transcript is imprinted. However, the recent identification of other imprinted transcripts encoded by GNAS1 and overlapping Gsα, together with at least one imprinted antisense transcript, raises intriguing questions about how the primary effect of mutations in GNAS1 might be modulated. Hum Mutat 16:183–189, 2000. © 2000 Wiley‐Liss, Inc.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

“…22 The presence of MRI appearance or pathological evidence of FCD in Cases 2 to 5 prompted assessment of increased mTOR activation, because classically FCDs have been associated with mTOR-related genetic abnormalities. 11,21,[33][34][35][36][37][38][39][40][41][42] Consistent with previous reports, we found low levels of baseline P-S6 immunoreactivity in control brain sections within scattered cortical neurons across all layers in the subpial region of layer I (Fig 4). 43,44 A similarly low level of baseline P-S6 labeling was observed in the SLC35A2-associated cases (see Fig 4), suggesting that SLC35A2 haploinsufficiency does not result in activation of mTOR signaling.…”

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

“…22 The presence of MRI appearance or pathological evidence of FCD in Cases 2 to 5 prompted assessment of increased mTOR activation, because classically FCDs have been associated with mTOR-related genetic abnormalities. 11,21,[33][34][35][36][37][38][39][40][41][42] Consistent with previous reports, we found low levels of baseline P-S6 immunoreactivity in control brain sections within scattered cortical neurons across all layers in the subpial region of layer I (Fig 4). 43,44 A similarly low level of baseline P-S6 labeling was observed in the SLC35A2-associated cases (see Fig 4), suggesting that SLC35A2 haploinsufficiency does not result in activation of mTOR signaling.…”

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

“…As GNAS sequencing has traditionally only been performed in individuals with classical clinical features, our findings suggest that the true prevalence in childhood obesity may be underappreciated. Three of the variants found in our study have been described previously in patients with classical features (p.Y163X 7 ; p.R258W 8 , and p.R265H 9 ). We identified a novel nonsense variant (p.Y169X) predicted to remove the entire Ras-like GTPase domain and several missense variants predicted to affect downstream signalling by affecting the interaction with G-protein coupled receptors (GPCRs), G-protein β- and γ-subunits, or downstream adenylyl cyclase when mapped onto the protein structure of GNAS (Fig.…”

14 Genetics of Congenital Hypothyroidism

“…73 G proteins mediate signal transduction across cell membranes, coupling extracellular receptors-including those binding TSH, TRH, parathyroid hormone (PTH), and luteinising hormone-to intracellular effector proteins such as ion channels and the adenylyl cyclase and phospholipase C second messenger systems. 74 Heterozygous inactivating mutations in GNAS1 result in Albright hereditary osteodystrophy. This is an autosomal dominant disorder characterised by recognisable dysmorphic features including short stature, shortened fourth and fifth metacarpals and metatarsals, obesity, subcutaneous ossification, intracranial calcification, and variable mental retardation.…”

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

“…22 The presence of MRI appearance or pathological evidence of FCD in Cases 2 to 5 prompted assessment of increased mTOR activation, because classically FCDs have been associated with mTOR-related genetic abnormalities. 11,21,[33][34][35][36][37][38][39][40][41][42] Consistent with previous reports, we found low levels of baseline P-S6 immunoreactivity in control brain sections within scattered cortical neurons across all layers in the subpial region of layer I (Fig 4). 43,44 A similarly low level of baseline P-S6 labeling was observed in the SLC35A2-associated cases (see Fig 4), suggesting that SLC35A2 haploinsufficiency does not result in activation of mTOR signaling.…”

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

“…As GNAS sequencing has traditionally only been performed in individuals with classical clinical features, our findings suggest that the true prevalence in childhood obesity may be underappreciated. Three of the variants found in our study have been described previously in patients with classical features (p.Y163X 7 ; p.R258W 8 , and p.R265H 9 ). We identified a novel nonsense variant (p.Y169X) predicted to remove the entire Ras-like GTPase domain and several missense variants predicted to affect downstream signalling by affecting the interaction with G-protein coupled receptors (GPCRs), G-protein β- and γ-subunits, or downstream adenylyl cyclase when mapped onto the protein structure of GNAS (Fig.…”

14 Genetics of Congenital Hypothyroidism

“…73 G proteins mediate signal transduction across cell membranes, coupling extracellular receptors-including those binding TSH, TRH, parathyroid hormone (PTH), and luteinising hormone-to intracellular effector proteins such as ion channels and the adenylyl cyclase and phospholipase C second messenger systems. 74 Heterozygous inactivating mutations in GNAS1 result in Albright hereditary osteodystrophy. This is an autosomal dominant disorder characterised by recognisable dysmorphic features including short stature, shortened fourth and fifth metacarpals and metatarsals, obesity, subcutaneous ossification, intracranial calcification, and variable mental retardation.…”

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

“…22 The presence of MRI appearance or pathological evidence of FCD in Cases 2 to 5 prompted assessment of increased mTOR activation, because classically FCDs have been associated with mTOR-related genetic abnormalities. 11,21,[33][34][35][36][37][38][39][40][41][42] Consistent with previous reports, we found low levels of baseline P-S6 immunoreactivity in control brain sections within scattered cortical neurons across all layers in the subpial region of layer I (Fig 4). 43,44 A similarly low level of baseline P-S6 labeling was observed in the SLC35A2-associated cases (see Fig 4), suggesting that SLC35A2 haploinsufficiency does not result in activation of mTOR signaling.…”

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

“…As GNAS sequencing has traditionally only been performed in individuals with classical clinical features, our findings suggest that the true prevalence in childhood obesity may be underappreciated. Three of the variants found in our study have been described previously in patients with classical features (p.Y163X 7 ; p.R258W 8 , and p.R265H 9 ). We identified a novel nonsense variant (p.Y169X) predicted to remove the entire Ras-like GTPase domain and several missense variants predicted to affect downstream signalling by affecting the interaction with G-protein coupled receptors (GPCRs), G-protein β- and γ-subunits, or downstream adenylyl cyclase when mapped onto the protein structure of GNAS (Fig.…”

14 Genetics of Congenital Hypothyroidism

“…73 G proteins mediate signal transduction across cell membranes, coupling extracellular receptors-including those binding TSH, TRH, parathyroid hormone (PTH), and luteinising hormone-to intracellular effector proteins such as ion channels and the adenylyl cyclase and phospholipase C second messenger systems. 74 Heterozygous inactivating mutations in GNAS1 result in Albright hereditary osteodystrophy. This is an autosomal dominant disorder characterised by recognisable dysmorphic features including short stature, shortened fourth and fifth metacarpals and metatarsals, obesity, subcutaneous ossification, intracranial calcification, and variable mental retardation.…”