MNX1 – Neonatal Diabetes Mellitus

MNX1 encodes a homeobox transcription factor essential for pancreatic β-cell differentiation. Neonatal diabetes mellitus (MONDO:0016391) presents with persistent hyperglycemia before six months of age. Two unrelated cases of permanent NDM were identified with homozygous MNX1 missense variants, p.Phe248Leu and p.Phe272Leu, implicating MNX1 in β-cell deficiency (PMID:29309627).

Genetically, both probands inherited their variants in an autosomal recessive pattern, with no additional affected relatives reported. These two independent cases provide limited genetic evidence for causality in NDM, consistent with ClinGen Limited classification due to small numbers of unrelated probands.

Functionally, the p.Phe248Leu mutant localized to the nucleus but lacked phosphorylation in MIN6 β-cells and altered cell proliferation, mirroring human β-cell loss in neonatal diabetes. This supports a loss-of-function mechanism via disrupted post-translational modification, yielding moderate experimental evidence.

Integrating the genetic and functional data, MNX1 homozygous missense variants disrupt β-cell maintenance leading to permanent NDM. While current evidence is limited by case count, concordant in vitro assays underpin clinical utility of MNX1 sequencing in early-onset diabetes. Key take-home: Autosomal recessive MNX1 variants should be considered in genetic work-up of neonatal diabetes.

References

• Endocrinology • 2018 • Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO. PMID:29309627

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