NEUROD1 and Monogenic Diabetes

Monogenic diabetes (MONDO:0015967) due to NEUROD1 variants (MODY6) has been reported in a small number of unrelated families and probands, consistent with an autosomal dominant inheritance pattern. Two heterozygous NEUROD1 mutations were identified in autoantibody‐negative pediatric diabetes cohorts: a frameshift variant c.617dup (p.His206GlnfsTer) in one proband detected by targeted NGS (10.5% of autoantibody‐negative subjects) (PMID:35769090) and a missense mutation c.317C>T (p.Ala106Val) in a Chinese MODY6 case report (PMID:40026692). Segregation of a novel p.Ser159Pro variant in one family co-segregated with diabetes in four additional affected relatives (PMID:17440689). No NEUROD1 mutations were found in a diagnostic screen of 73 Norwegian MODYX probands and 51 gestational diabetes subjects, indicating mutation rarity and low prevalence in some populations (PMID:16026366).

Functional studies demonstrate that NEUROD1 acts as a key regulator of insulin gene transcription and β-cell differentiation. Chromatin immunoprecipitation and promoter assays confirmed direct NEUROD1 binding to the Ins2 promoter, and siRNA knockdown of Neuronatin (a NEUROD1 target) impaired glucose‐mediated insulin secretion in β‐cells (PMID:15793245). NEUROD1 interacts with PDX1 and MafA to modulate Ins2 expression, with loss-of-function reducing insulin mRNA in islet cells (PMID:19264802). Recent knockout models show Neurod1 deficiency disrupts endocrine lineage commitment, confirming a haploinsufficiency mechanism for neonatal diabetes and MODY (PMID:37689751).

References

• Frontiers in endocrinology • 2025 • A case report of a MODY6 patient coexistence with Charcot-Marie-Toothe 1A syndrome. PMID:40026692
• Journal unknown • Year unknown • Prevalence of monogenic diabetes in pediatric insulin-dependent patients PMID:35769090
• Molecular and cellular biochemistry • 2007 • A novel mutation, Ser159Pro in the NeuroD1/BETA2 gene contributes to the development of diabetes in a Chinese potential MODY family. PMID:17440689
• Diabetic medicine • 2005 • Diagnostic screening of NEUROD1 (MODY6) in subjects with MODY or gestational diabetes mellitus. PMID:16026366
• Diabetes • 2005 • Neuronatin, a downstream target of BETA2/NeuroD1 in the pancreas, is involved in glucose-mediated insulin secretion. PMID:15793245
• Nucleic acids research • 2009 • The Krüppel-like zinc finger protein Glis3 directly and indirectly activates insulin gene transcription PMID:19264802
• Nature communications • 2023 • NEUROD1 reinforces endocrine cell fate acquisition in pancreatic development. PMID:37689751

Evidence Based Scoring (AI generated)