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UFD1 – Schizophrenia

UFD1 (HGNC:12520) has been implicated in schizophrenia (MONDO:0005090) via multi‐patient association studies. In one study, gene expression profiling of 394 individuals revealed that UFD1 expression was significantly upregulated in both clinical high‐risk and chronic schizophrenia patients compared to first episode patients (PMID:30923314). Another study, though primarily focused on neighboring genes, suggested that regional haplotype analyses in the 22q11.2 region are associated with cognitive performance impairments in schizophrenia (PMID:31193788). The absence of robust segregation data and clearly pathogenic coding variants tempers the overall genetic support, thereby categorizing the gene–disease association as Limited.

Functional evidence further supports a potential mechanistic contribution of UFD1 to cellular processes relevant to schizophrenia. Experimental studies demonstrated that phosphorylation at serine 229 of UFD1 negatively regulates its binding with VCP, a critical interaction in endoplasmic reticulum‐associated degradation, thereby perturbing protein homeostasis (PMID:31477623). Although these functional assays do not directly link UFD1 regulation to the pathogenesis of schizophrenia, they offer important biological insight that complements the genetic findings. Key take‐home sentence: Integrating both genetic associations and functional mechanistic data, UFD1 emerges as a promising, though currently limited, candidate for refining diagnostic and therapeutic strategies in schizophrenia.

References

  • Schizophrenia research. Cognition • 2019 • Association of genetic variants at 22q11.2 chromosomal region with cognitive performance in Japanese patients with schizophrenia PMID:31193788
  • NPJ schizophrenia • 2019 • Gene expression over the course of schizophrenia: from clinical high‑risk for psychosis to chronic stages PMID:30923314
  • The Biochemical journal • 2019 • Ufd1 phosphorylation at serine 229 negatively regulates endoplasmic reticulum‑associated degradation by inhibiting the interaction of Ufd1 with VCP PMID:31477623

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Association is suggested by differential gene expression in schizophrenia cohorts and regional haplotype analyses (PMID:30923314, PMID:31193788) but is limited by the absence of Mendelian segregation and clearly pathogenic variants.

Genetic Evidence

Limited

Genetic data derive primarily from expression studies without definitive pathogenic variants, providing only limited evidence of a direct association.

Functional Evidence

Moderate

Functional assays demonstrate that phosphorylation of Ufd1 modulates its interaction with VCP and ER-associated degradation, supplying mechanistic support for the gene's biological relevance (PMID:31477623).