A complex pheotype in a girl with a novel heterozygous missense variant (p.Ile56Phe) of the GNAS gene

Orphanet Journal of Rare Diseases

Susanne Thiele¹  Peverelli Erika²  Francesca Marta Elli²  Mantovani Giovanna²  Granata Francesca³  Gastaldi Andrea⁴  Antoniazzi Franco⁴  Gaudino Rossella⁴  Brugnara Milena⁴  Cavarzere Paolo⁴ 

[1] Division of Paediatric Endocrinology and Diabetes, Department of Pediatrics, University of Lübeck;Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico;General Medicine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico;Pediatric Division, Department of Pediatrics, University Hospital of Verona;

关键词: GNAS gene;    Hyponatremia;    Subclinical hyperthyroidism;    Precocious thelarche;    Congenital bone abnormalities;   

DOI  :  10.1186/s13023-022-02252-6

来源: DOAJ

【 摘 要 】

Abstract Background GNAS is a complex gene that encodes Gsα, a signaling protein that triggers a complex network of pathways. Heterozygous inactivating mutations in Gsα-coding GNAS exons cause hormonal resistance; on the contrary, activating mutations in Gsα result in constitutive cAMP stimulation. Recent research has described a clinical condition characterized by both gain and loss of Gsα function, due to a heterozygous de novo variant of the maternal GNAS allele. Patients and methods We describe a girl with a complex combination of clinical signs and a new heterozygous GNAS variant. For the molecular analysis of GNAS gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples. In silico analysis was performed to predict the possible in vivo effect of the detected novel genetic variant. The activity of Gsα protein was in vitro analyzed from samples of erythrocyte membranes, recovered from heparinized blood samples. Results We found a new heterozygous missense c.166A > T—(p.Ile56Phe) GNAS variant in exon 2, inherited from the mother that determined a reduced activity of 50% of Gsα protein function. The analysis of her parents showed a 20–25% reduction in Gsα protein activity in the mother and a normal function in the father. Clinically our patient presented a multisystemic disorder characterized by hyponatremia compatible with a nephrogenic syndrome of inappropriate antidiuresis, subclinical hyperthyroidism, subclinical hypercortisolism, precocious thelarche and pubarche and congenital bone abnormalities. Conclusions This is the first time that the new variant c.166A > T (p.Ile56Phe) on exon 2 of GNAS gene, originated on maternal allele, has been described as probable cause of a multisystemic disorder. Although the mutation is associated with a reduced activity of the function of Gsα protein, this unusual phenotype on the contrary suggests a mild functional gain.

【 授权许可】

Unknown