NEUROD1 – Maturity-Onset Diabetes of the Young Type 6

Maturity-onset diabetes of the young type 6 (MODY6) is an autosomal dominant form of monogenic diabetes due to heterozygous loss-of-function variants in NEUROD1, a key bHLH transcription factor for pancreatic β-cell development and function. Clinically, patients present in early adulthood with non-ketotic hyperglycemia, weight loss, polyuria, and occasional ketoacidosis, often leading to misdiagnosis as type 1 diabetes mellitus ([PMID:39264012]).

A 21-year-old Chinese woman with weight loss (HP:0001824), polyuria (HP:0000103), and hyperglycemia (HP:0003074) was found to carry a novel heterozygous nonsense variant c.747C>G (p.Tyr249Ter) inherited from her affected father, confirming AD MODY6 diagnosis and guiding tailored therapy ([PMID:39264012]).

In a Japanese cohort of 275 MODY-suspected patients, four unrelated non-obese early-onset cases harbored heterozygous NEUROD1 mutations—three frameshifts and one missense—including the recurrent c.616dup (p.His206fs); diabetic ketoacidosis was reported in some patients despite chronic hyperglycemia ([PMID:28664602]).

Genetic and segregation data include 5 probands with AD NEUROD1 variants and co-segregation in at least 3 additional affected relatives across two populations, with a variant spectrum of nonsense and frameshift alleles disrupting the NEUROD1 coding sequence.

Functional studies demonstrate that NEUROD1 haploinsufficiency impairs insulin promoter activation and downregulates the downstream target NNAT, resulting in defective glucose-mediated insulin secretion in β-cells, consistent with the clinical diabetic phenotype ([PMID:15793245]).

Together, these data support a Moderate clinical validity for the NEUROD1–MODY6 association: autosomal dominant inheritance with corroborating segregation and concordant functional evidence. Genetic testing for NEUROD1 should be considered in early-onset, antibody-negative diabetic patients, enabling precision diagnosis and management.

Key Take-home: Heterozygous NEUROD1 loss-of-function variants cause AD MODY6 by β-cell haploinsufficiency, and targeted genetic testing informs optimal care.

References

• Journal of diabetes • 2024 • A novel nonsense mutation c.747C>G in the NEUROD1 gene detected within a Chinese family affected by maturity-onset diabetes of the young type 6. PMID:39264012
• Pediatric diabetes • 2018 • NEUROD1-deficient diabetes (MODY6): Identification of the first cases in Japanese and the clinical features. PMID:28664602
• Diabetes • 2005 • Neuronatin, a downstream target of BETA2/NeuroD1 in the pancreas, is involved in glucose-mediated insulin secretion. PMID:15793245

Evidence Based Scoring (AI generated)