HNF1B – Permanent Neonatal Diabetes Mellitus

Heterozygous mutations in HNF1B have been implicated in permanent neonatal diabetes mellitus (PNDM), often arising de novo and following an autosomal dominant inheritance pattern. In a cohort of nine Qatari patients with PNDM, one individual harbored a novel de novo HNF1B variant, consistent with a disease incidence of 1:22 938 live births in this population ([PMID:31441606]). No additional familial segregation was observed, and the variant spectrum in PNDM remains limited to single case reports, supporting a limited clinical validity at present.

Functional studies of HNF1B demonstrate that loss-of-function mutations disrupt pancreatic development and insulin secretion. For example, the missense change c.451T>C (p.Ser151Pro) abolishes DNA binding and transcriptional activation in vitro ([PMID:10484768]). In Xenopus embryos, frameshift and deletion mutants similarly impair pronephros and pancreatic morphogenesis, recapitulating aspects of human disease ([PMID:10758154]). These data collectively support haploinsufficiency as the mechanism of pathogenicity.

Key take-home: While HNF1B mutations can cause PNDM via haploinsufficiency, current evidence is limited to single-case reports; further studies are needed to establish diagnostic utility and variant spectrum.

References

• Molecular genetics & genomic medicine • 2019 • The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Qatar. PMID:31441606
• Human molecular genetics • 1999 • A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. PMID:10484768
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • The mutated human gene encoding hepatocyte nuclear factor 1beta inhibits kidney formation in developing Xenopus embryos. PMID:10758154

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