INS – Maturity-Onset Diabetes of the Young Type 10 (MODY10)

Heterozygous mutations in the insulin gene (INS) are causative for MODY10 (MONDO:0013240), an autosomal dominant, non-autoimmune form of early-onset diabetes characterized by fasting hyperglycemia, elevated HbA₁c, low C-peptide, and negative islet autoantibodies. Genetic testing is therefore critical for precise diagnosis and management.

A novel heterozygous frameshift–nonsense variant, c.309_314delinsGCGC (p.Tyr103Ter), was identified in a 2-year-old Chinese boy with fasting glucose 8.1–10.7 mmol/L and glycosylated hemoglobin 8.5%. Family sequencing confirmed maternal transmission; his mother had childhood-onset diabetes with microvascular complications ([PMID:33194056]).

An INS signal peptide variant, c.4G>A (p.Ala2Thr), co-segregated with diabetes in a Chinese MODY pedigree. Functional studies in INS-1 cells revealed impaired signal peptide cleavage, reduced glucose-stimulated insulin secretion, and increased endoplasmic reticulum (ER) stress ([PMID:32405973]).

The missense mutation c.137G>A (p.Arg46Gln; GlnB22-insulin) has been structurally and functionally characterized. Chemically synthesized mutant proinsulin exhibited defective folding, decreased receptor affinity, and ~20% of wild-type bioactivity in vitro ([PMID:25423173]); in an 18-year-old MODY patient, mutant insulin was secreted at 1.5× wild-type levels with 57% receptor affinity ([PMID:28478482]).

Collectively, at least three independent heterozygous INS variants in two unrelated pedigrees show co-segregation with early-onset diabetes, with concordant functional assays demonstrating proinsulin misfolding, a dominant-negative mechanism, ER stress, and impaired secretion.

Scores

• gene_disease_association: Moderate; 2 families, 3 probands, co-segregation in multi-generation pedigrees, concordant functional data.
• genetic_evidence: Moderate; heterozygous LoF and missense variants in independent pedigrees co-segregate with disease.
• functional_evidence: Moderate; cell-based and biochemical assays demonstrate impaired proinsulin folding, ER stress, and reduced insulin secretion.

Key Take-home: INS sequencing should be included in the diagnostic workup of early-onset, autoantibody-negative diabetes to enable precise Mendelian diagnosis and treatment planning.

References

• American journal of translational research • 2020 • MODY10 caused by c.309-314del CCAGCT insGCGC mutation of the insulin gene: a case report. PMID:33194056
• PLoS one • 2014 • Structural and functional study of the GlnB22-insulin mutant responsible for maturity-onset diabetes of the young. PMID:25423173
• Molecular and cellular biochemistry • 2020 • Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family. PMID:32405973
• Diabetologia • 2017 • In vivo measurement and biological characterisation of the diabetes-associated mutant insulin p.R46Q (GlnB22-insulin). PMID:28478482

Evidence Based Scoring (AI generated)