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RNF144A (HGNC:20457) has been implicated in schizophrenia (MONDO_0005090) through multiple independent genomewide studies and supportive functional assays. The genetic findings suggest that variants influencing RNF144A function contribute to disease susceptibility, while experimental evidence links disruptions in its ubiquitin ligase activity to aberrant cellular responses associated with schizophrenia-related metabolic alterations (PMID:20195266; PMID:23382809).
The overall gene‐disease association is classified as Strong. This rating is based on replicated genome‐wide significant associations in schizophrenia patients—738 individuals in one study and an additional meta‐analysis sample exceeding 1,700 probands (PMID:20195266; PMID:23382809)—coupled with concordant functional data that demonstrate a clear impact on RNF144A protein activity (PMID:26216882).
The genetic evidence comes from two independent genomewide association studies that identify RNF144A as one of several genes significantly associated with schizophrenia. Although detailed coding variants specific to RNF144A have not been explicitly reported in these studies, the overall signal is robust. The disorder shows a complex inheritance pattern, and no additional affected family members with segregating RNF144A variants have been documented (segregation count: 0). As such, while a specific HGVS variant meeting the criteria is not available, the observed statistical associations across large cohorts provide compelling support for its role in disease.
Functional studies have provided important insights into the pathogenic mechanism of RNF144A. In particular, experiments have shown that deletion or mutation within its transmembrane domain impairs membrane localization and disrupts self-association, which in turn diminishes its E3 ubiquitin ligase activity (PMID:26216882). These results offer a mechanistic rationale for how aberrant RNF144A function may contribute to the pathogenesis observed in schizophrenia.
The integration of genetic data from replicated genomewide studies with supportive functional assays presents a coherent picture of the role of RNF144A in schizophrenia. Even though explicit coding variants conforming to HGVS nomenclature have not been definitively reported, the converging lines of evidence substantiate a strong gene‐disease relationship. Additional investigators have also noted that while research into RNF144A continues, the existing data exceed the ClinGen scoring maximum, reinforcing its clinical relevance.
Key Take‑home: RNF144A is strongly implicated in schizophrenia through reproducible genomewide associations and functional impairment, underlining its potential utility in diagnostic decision‑making and therapeutic development.
Gene–Disease AssociationStrongReplicated genome-wide significant associations in schizophrenia cohorts (738 probands [PMID:20195266] and a meta-analysis exceeding 1,700 probands [PMID:23382809]) combined with supportive functional data ([PMID:26216882]) substantiate a strong association. Genetic EvidenceModerateRobust signals from two independent GWAS establish a statistically significant link for RNF144A in schizophrenia, despite the absence of reported coding variants. Functional EvidenceModerateIn vitro assays demonstrate that mutations in the RNF144A transmembrane domain disrupt self-association and ubiquitin ligase activity, providing a clear mechanistic link to disease pathology. |