OLFM1 – Type 2 Diabetes Mellitus

Multiple independent studies have reported an association between variants in OLFM1 (HGNC:17187) and type 2 diabetes mellitus (MONDO:0005148). In the initial study, a missense mutation, identified as S20G, was observed in 12 unrelated patients with non‑insulin‑dependent diabetes mellitus, with 8 of these patients having an early disease onset and strong family histories (PMID:8772735). This finding provided the first evidence of a functional role for an OLFM1 mutation in diabetes susceptibility.

Subsequent case‑control studies involving larger cohorts further reinforced the link. One study screened 1,538 type 2 diabetic patients and 1,108 controls across multiple centers in Japan, demonstrating that the S20G mutation occurred at a significantly higher frequency in patients (2.6%) compared to controls (0.8%), supporting an association with increased risk (PMID:11508277). Another study in the New Zealand Maori population reported similar findings, with additional mutations in the promoter and coding regions contributing to the overall genetic risk, confirming that OLFM1 variations predispose carriers to type 2 diabetes (PMID:12679865).

A third independent study in a Korean cohort revealed that diabetic patients carrying the S20G mutation exhibited a lower body mass index and higher HbA1c levels compared to non‑carriers, further emphasizing the clinical impact of this allele in disease presentation (PMID:12706321). Collectively, these multi‑patient studies establish a robust genetic association between OLFM1 variants and type 2 diabetes mellitus.

Functional assessment studies have provided key mechanistic insights. In vitro experiments using COS‑1 cells demonstrated that the S20G variant leads to significantly increased amyloid fibril formation and heightened cytotoxicity compared to the wild‑type peptide, implicating increased amyloidogenicity as a plausible pathogenic mechanism (PMID:11106582). In parallel, structural analyses evaluated the impact of the S20G alteration on amylin hormone folding and aggregation, further substantiating its deleterious effect on protein function (PMID:34044067).

The mode of inheritance appears to be consistent with an autosomal dominant susceptibility, as the mutation is reported in the heterozygous state across diverse populations and segregates with the diabetic phenotype in affected families. Although quantitative segregation data are limited, the noted strong family histories in the initial report provide additional support for a heritable component.

Integrated assessment of both genetic and experimental evidence supports a strong gene‑disease association. The convergence of multiple, large‑scale case–control studies and functional assays confirms the pathological role of the S20G mutation. This level of evidence is clinically actionable for diagnostic decision‑making and may facilitate the development of personalized therapeutic strategies.

Key Take‑home: The OLFM1 S20G mutation represents a significant, functionally validated risk factor for type 2 diabetes mellitus, with important implications for clinical risk assessment and targeted treatment strategies.

References

• Diabetes • 1996 • Missense mutation of amylin gene (S20G) in Japanese NIDDM patients PMID:8772735
• Diabetologia • 2001 • S20G mutation of the amylin gene is associated with Type II diabetes in Japanese. Study Group of Comprehensive Analysis of Genetic Factors in Diabetes Mellitus PMID:11508277
• Diabetologia • 2003 • Amylin gene promoter mutations predispose to Type 2 diabetes in New Zealand Maori PMID:12679865
• Diabetes Research and Clinical Practice • 2003 • S20G mutation of the amylin gene is associated with a lower body mass index in Korean type 2 diabetic patients PMID:12706321
• The American Journal of Pathology • 2000 • S20G mutant amylin exhibits increased in vitro amyloidogenicity and increased intracellular cytotoxicity compared to wild‑type amylin PMID:11106582
• Biochimica et Biophysica Acta. General Subjects • 2021 • Structural effects driven by rare point mutations in amylin hormone, the type II diabetes‑associated peptide PMID:34044067

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