GNAS Complex Locus

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OMIM Number

139320

NCBI Gene ID

2778

Uniprot ID

Q5JWF2

Length

71,516 bases

No. of Exons

23

No. of isoforms

3

Protein Name

Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas

Molecular Mass

111025 Da

Amino Acid Count

1037

Genomic Location

chr20:58,839,681-58,911,196

Gene Map Locus
20q13.32

Description

GNAS gene encodes the stimulatory alpha subunit of a protein complex called a guanine nucleotide-binding protein (G protein). G proteins are involved in signal transduction, the process of transmitting signals from a variety of stimuli outside a cell to its interior. The G protein containing the GNAS encoded subunit is responsible for stimulating the activity of the adenylate cyclase enzyme. As adenylate cyclase is believed to play a key role in signaling pathways that help regulate osteogenesis and hormone production, the G protein is essential for the regulation of these processes.

GNAS is associated with several disorders, namely: somatic acromegaly, ACTH-independent macronodular adrenal hyperplasia, somatic mosaic McCune-Albright syndrome, progressive osseous heteroplasia, pseudohypoparathyroidism (types Ia, Ib and Ic) and pseudopseudohypoparathyroidism. 

Molecular Genetics

GNAS is a complex imprinted locus and the presence of alternative promoters as well as alternative splicing results in multiple isoforms of the protein. The Gs-alpha transcript, responsible for encoding the alpha subunit of the stimulatory guanine nucleotide-binding protein, is expressed biallelically in most tissues of the body. The remaining GNAS transcripts are all expressed exclusively from either the paternal or maternal allele. Inactivating loss-of-function mutations in the GNAS1 gene result in pseudohypoparathyroidism IA, pseudopseudohypoparathyroidism, and progressive osseous heteroplasia, while activating gain-of-function mutations in the GNAS1 gene result in McCune-Albright syndrome, polyostotic fibrous dysplasia, and various endocrine tumors.    

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_000516.5:c.212+1304=United Arab EmiratesNC_000020.11:g.58896988=AssociationType 2 Diabetes Mellitus; ObesityNG_016194.2:g.62249= ; NM_000516.5:c.212+1304=; NP_000507.1:p.?2057291
NM_001077490.3:c.1046C>TLebanonchr20:58854498Uncertain SignificanceBreast CancerNG_016194.2:g.19759C>T; NM_001077490.3:c.1046C>T; NP_001070958.1:p.Pro349Leu373809205
NM_080425.4:c.2405T>CSaudi ArabiaNC_000020.11:g.58905426T>CPathogenicPseudohypoparathyroidism, Type IANG_016194.2:g.70687T>C; NM_080425.4:c.2405T>C; NP_536350.2:p.Val802Ala

Other Reports

Saudi Arabia

Anazi et al. (2017) attempted to study the effectiveness of genomic tools in the diagnosis of Intellectual Disability (ID) cases. 337 ID patients were subjected to molecular karyotyping, exome sequencing or sequencing by a gene panel comprised of neurologically associated genes. Genomic tools were found to have a higher diagnostic yield than standard clinical evaluations (58% vs 16%). In one patient, the analysis helped uncover a de novo mutation (c.2405T>C, p.Val802Ala) in the GNAS gene. It was further noted that the patient presented atypical features not consistent with a GNAS phenotype such as metopic craniosynostosis, hydronephrosis, brain heterotopia, thinning of corpus callosum and thyroid agenesis.

Maddirevula et al., 2018 reported a male patient with pseudohypoparathyroidism, type IB. Patient had recurrent fractures, scoliosis, osteopenia, and pes planus. His parents were nonconsanguineous. Methylation-specific-MLPA revealed hypomethylation of the maternal GNAS  allele.

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