The role of genetic and epigenetic GNAS alterations in the development of early-onset obesity

Abbas, Alaa; Hammad, Ayat S; Al-Shafai, Mashael

doi:10.1016/j.mrrev.2023.108487

Mutation Research - Reviews in Mutation Research

2024

DOI: 10.1016/j.mrrev.2023.108487

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The role of genetic and epigenetic GNAS alterations in the development of early-onset obesity

Alaa Abbas,

Ayat S Hammad,

Mashael Al-Shafai

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2024

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Cited by 1 publication

References 157 publications

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gnas Knockdown Induces Obesity and AHO Features in Early Zebrafish Larvae

Abbas,

Hammad,

Zakaria

et al. 2024

IJMS

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GNAS (Guanine Nucleotide-Binding Protein, Alpha Stimulating) is a complex gene that encodes the alpha subunit of the stimulatory G protein (Gsα), critical for signaling through various G protein-coupled receptors. Inactivating genetic and epigenetic changes in GNAS, resulting in Gsα deficiency, cause different variants of pseudohypoparathyroidism, which may manifest features of Albright hereditary osteodystrophy (AHO, a syndrome characterized by early-onset obesity and other developmental defects). Recent findings have linked Gsα deficiency with isolated, severe, early-onset obesity, suggesting it as a potential, underrecognized cause of monogenic, non-syndromic obesity. This study was prompted by identifying several GNAS variants of uncertain significance (VUSs) in pediatric patients presenting with unexplained, severe, early-onset obesity at Sidra Medicine in Qatar. To functionally characterize these variants, we developed the first zebrafish model of Gsα deficiency, offering numerous advantages over other model systems. This was achieved by knockdown of the ortholog through microinjection of translation-blocking Morpholino antisense oligonucleotides into the yolks of 1-8-cell-stage zebrafish embryos. The morphant larvae displayed an obese phenotype, marked by significantly enlarged yolk sacs, increased neutral lipid accumulation, and reduced metabolic rates, among other developmental abnormalities resembling those in AHO. This zebrafish model lays the foundation for efficient functional characterization of GNAS VUSs and paves the way for enhancing our understanding of Gsα deficiency-associated early-onset obesity.

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gnas Knockdown Induces Obesity and AHO Features in Early Zebrafish Larvae

Abbas,

Hammad,

Zakaria

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

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The role of genetic and epigenetic GNAS alterations in the development of early-onset obesity

Cited by 1 publication

References 157 publications

gnas Knockdown Induces Obesity and AHO Features in Early Zebrafish Larvae

gnas Knockdown Induces Obesity and AHO Features in Early Zebrafish Larvae

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