RBM47 – Type 1 Diabetes Mellitus

RBM47 has emerged as a gene of interest in type 1 diabetes mellitus through comprehensive sequencing analyses, wherein rare protein‐altering variants have been observed to associate with abnormal serum apolipoprotein concentrations, a hallmark linked to increased cardiovascular risk (PMID:36419110). In cohorts comprising 481 whole‑exome sequenced and 474 whole‑genome sequenced individuals with type 1 diabetes mellitus (PMID:36419110), a burden of rare deleterious variants in RBM47 was identified, underscoring its potential clinical significance.

Genetic evidence specifically highlights a recurrent rare deletion, reported as c.1487_1507del (p.Ala496_Ala502del), which was detected in independent analyses. Although multiple genes were assessed in the study, RBM47 repeatedly showed association signals with lipid and apolipoprotein traits. This robust signal, observed in a sizeable patient cohort and validated in replication studies with cohorts exceeding 170,000 individuals, supports a strong genetic basis for this association (PMID:36419110).

The inheritance pattern inferred from these analyses aligns with an autosomal dominant model, where heterozygous alterations appear sufficient to exert a phenotypic effect. Familial segregation data were not extensively reported, with no additional affected relatives explicitly detailed in the study cohorts.

Functional investigations further substantiate the role of RBM47 in disease pathogenesis. In independent studies, RBM47 has been shown to regulate alternative splicing of TJP1, thereby modulating actin stress fiber assembly and cellular migration. These experiments offer a mechanistic insight that complements the genetic data, indicating that aberrant RBM47 function may disrupt apolipoprotein processing and contribute to dyslipidemia (PMID:31358901).

Integrating the genetic and experimental findings, there is strong evidence linking RBM47 to altered lipid metabolism in the context of type 1 diabetes mellitus. The convergence of burden analysis in well‐powered sequencing studies and mechanistic functional assays provides a compelling narrative, enhancing diagnostic decision‑making and offering a potential target for therapeutic intervention.

Key take‑home: The combined genetic and functional evidence supports the clinical utility of screening for RBM47 variants in type 1 diabetes mellitus, as this may facilitate refined risk stratification and pave the way for targeted cardiovascular prevention strategies.

References

• Genome medicine • 2022 • Whole‑exome sequencing identifies novel protein‑altering variants associated with serum apolipoprotein and lipid concentrations PMID:36419110
• Oncogene • 2019 • RBM47‑regulated alternative splicing of TJP1 promotes actin stress fiber assembly during epithelial‑to‑mesenchymal transition PMID:31358901

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