GATA6 – Neonatal Diabetes Mellitus

GATA6 encodes a zinc-finger transcription factor critical for pancreatic organogenesis and β-cell function. Heterozygous loss-of-function variants in GATA6 cause permanent neonatal diabetes mellitus ([PMID:22962692]), typically via pancreatic agenesis or severe hypoplasia. The inheritance is autosomal dominant with variable expressivity and penetrance.

Initial case reports described de novo frameshift and nonsense mutations leading to complete pancreatic agenesis and neonatal lethality ([PMID:22962692]). Subsequent reports identified heterozygous GATA6 variants in adult-onset diabetes with partial pancreatic hypoplasia ([PMID:32245430]) and familial mosaicism transmitting a novel c.635_660del (p.Pro212fs) variant to three affected siblings ([PMID:28049534]).

A cohort study of 795 neonatal diabetes patients found GATA6 mutations in 24 probands, representing the most common genetic cause of pancreatic agenesis in that series ([PMID:23223019]). Variant spectrum comprises frameshift (e.g., c.1504_1505del (p.Lys502fs)), nonsense (e.g., c.1502C>G (p.Ser501Ter)), and missense changes, all predicted to result in haploinsufficiency.

Segregation analysis documented transmission in three unrelated families with complete co-segregation of diabetes and pancreatic hypoplasia ([PMID:28049534]), and adult carriers with mild diabetes or subclinical exocrine insufficiency have been described ([PMID:23223019]).

Functional studies demonstrate that premature stop codons trigger nonsense-mediated mRNA decay in patient cells ([PMID:24310933]), and in vitro assays show reduced transactivation of pancreatic promoters. Animal and stem cell models confirm GATA6 haploinsufficiency disrupts pancreatic progenitor differentiation.

In summary, autosomal dominant GATA6 haploinsufficiency is a definitive cause of neonatal diabetes mellitus through pancreatic agenesis or hypoplasia. Genetic testing for GATA6 informs diagnosis, guides management, and enables familial risk assessment.

References

• Journal of medical genetics • 2012 • Dominantly inherited diabetes mellitus caused by GATA6 haploinsufficiency: variable intrafamilial presentation. PMID:22962692
• Diabetes • 2013 • GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency. PMID:23223019
• Diagnostic pathology • 2017 • Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus. PMID:28049534
• American journal of medical genetics. Part A • 2014 • A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay. PMID:24310933

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