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

The INS gene encodes insulin, a key peptide hormone regulating glucose homeostasis. Heterozygous mutations in INS drive a rare autosomal dominant subtype of maturity-onset diabetes of the young (MODY10), presenting in childhood or adolescence with variable insulin deficiency and often misdiagnosed as type 1 diabetes. Genetic testing for INS is recommended in antibody-negative patients with non-obese diabetes onset below 25 years.

Genetic evidence for the INS–MODY10 association includes multiple unrelated case series and cohort studies. Novel heterozygous missense, frameshift, and intronic INS variants have been described in >30 probands across multi-generation pedigrees, with segregation in >19 additional affected relatives displaying autosomal dominant inheritance (PMID:25721872, PMID:29633446). The variant spectrum encompasses coding changes (e.g., c.277G>A (p.Glu93Lys) (PMID:29633446)), de novo events, and recurrent alleles such as p.Arg46Gln. Population screening of 296 MODY probands and 285 early-onset diabetes cases confirmed INS mutations as a rare cause of MODY (0.7–1.4% frequency) but a common cause of permanent neonatal diabetes (PMID:18162506).

Experimentally, INS mutations often impair proinsulin folding and processing via dominant-negative mispaired disulfide bonds, culminating in endoplasmic reticulum stress and β-cell apoptosis. Functional assays in clonal β-cells and transgenic zebrafish demonstrate intracellular retention of misfolded proinsulin and reduced insulin secretion, while KLF11-dependent promoter mutations disrupt transcriptional activation of insulin (PMID:20007936, PMID:21592955). Mouse models of KLF11 deficiency recapitulate impaired glucose tolerance, underscoring transcriptional dysregulation in mutant INS mechanisms.

No substantial conflicting evidence has emerged; INS variants consistently co-segregate with MODY phenotypes and functional perturbations correlate with clinical severity. De novo cases and variable expressivity highlight the phenotypic spectrum but do not weaken the core gene–disease link.

In summary, autosomal dominant INS mutations confer a strong and clinically actionable risk for MODY10, validated by robust genetic segregation and mechanistic experimental data. Early molecular diagnosis enables precision management, including tailored insulin or non-insulin therapies based on variant effects.

Key Take-home: INS genetic testing should be integrated into diagnostic algorithms for early-onset, antibody-negative diabetes to inform optimal treatment and genetic counseling.

References

• European journal of medical genetics • 2015 • Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young. PMID:25721872
• Pediatric diabetes • 2018 • A novel INS mutation in a family with maturity-onset diabetes of the young: Variable insulin secretion and putative mechanisms. PMID:29633446
• Diabetes • 2008 • Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. PMID:18162506
• Diabetes • 2010 • Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. PMID:20007936
• The Journal of biological chemistry • 2011 • Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. PMID:21592955

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