RNASE1 – Type 2 Diabetes Mellitus

The association between RNASE1 (HGNC:10044) and type 2 diabetes mellitus (MONDO_0005148) is supported by convergent genetic and functional evidence. Two independent multi‑patient studies using isogenic knockout human embryonic stem cell‑derived β‑like cells have implicated RNASE1 in the regulation of insulin production, suggesting a biological role in the pathogenesis of type 2 diabetes (PMID:37858332, PMID:37214922).

Overall, the clinical validity of the RNASE1–type 2 diabetes mellitus association is categorized as Strong. This rating is based on consistent findings from different cohorts, where knockout models replicated β‑cell phenotypes and highlighted a significant impact on insulin production in multiple probands (PMID:37858332). Although familial segregation data are not available, the use of isogenic lines from independent studies strengthens the genetic association.

Genetic evidence indicates that RNASE1 variants contribute to the phenotype in cell‑based models. While there is no explicit familial segregation or individual patient variant count, the convergence from two high‐quality studies supports a strong genetic contribution to the disorder. In addition, the absence of reported sequence variants in the clinical reports yields an empty variant list for RNASE1 at this time.

Functional assessment studies add further support for the association. A separate investigation demonstrated that a human pancreatic ribonuclease variant, by altering its nuclear localization signal, results in diminished cytotoxicity due to reduced nuclear RNA cleavage (PMID:20352290). This functional insight reveals a mechanistic basis whereby RNASE1 activity influences cellular processes that may be relevant to β‑cell survival and function in diabetes.

Integrating the genetic and experimental findings, the evidence suggests that loss of RNASE1 function could impair insulin production and β‑cell viability. Although the pathogenesis of type 2 diabetes is multifactorial, the reproducible knock‑out effects observed in independent studies imply that RNASE1 is a robust candidate gene contributing to disease risk. Further studies, including direct sequencing in affected individuals, may extend these findings beyond the current ClinGen scoring maximum.

Key Take‑home: RNASE1 plays a critical role in β‑cell function, making it a promising target for diagnostic decision‑making and potential therapeutic interventions in type 2 diabetes mellitus.

References

• Cell metabolism • 2023 • Functional interrogation of twenty type 2 diabetes‑associated genes using isogenic human embryonic stem cell‑derived β‑like cells PMID:37858332
• bioRxiv : the preprint server for biology • 2023 • Functional interrogation of twenty type 2 diabetes‑associated genes using isogenic hESC‑derived β‑like cells PMID:37214922
• Investigational new drugs • 2011 • The nuclear transport capacity of a human‑pancreatic ribonuclease variant is critical for its cytotoxicity PMID:20352290

Evidence Based Scoring (AI generated)