DPYSL2 – Schizophrenia

DPYSL2 has been implicated in schizophrenia through transmission/disequilibrium testing in Ashkenazi Jewish case–parent trios, where DPYSL2 met association criteria in 274 schizophrenia trios (P < .01) ([PMID:16380905]). Subsequent sequencing of 14 exons and 27 conserved noncoding regions in 137 cases and 151 controls, followed by genotyping in 729 cases and 1542 controls, identified a 3-SNP promoter haplotype, two intron 1 SNPs, and a polymorphic CT dinucleotide repeat (DNR) in the 5′-UTR significantly associated with schizophrenia ([PMID:25416705]). A de novo burden test in 23 Han Chinese families also highlighted DPYSL2 among ten genes carrying a higher DNM rate in patients versus unaffected siblings ([PMID:32873781]). However, large-scale case–control studies in Japanese (n = 1464 patients, 1310 controls) and Chinese Han (n = 2552) cohorts failed to replicate any SNP or expression associations ([PMID:20414250]; [PMID:16321170]).

Functional assays provide moderate support for DPYSL2’s pathogenic role. The high-risk CT-DNR allele reduced reporter expression by 3–4-fold and retained differential response to rapamycin, linking DPYSL2 regulation to mTOR signaling ([PMID:25416705]). Electrophoretic mobility shift assays confirmed differential binding of mTOR effectors, including HuD/ELAVL4, to the DNR alleles, and CRISPR/Cas9 editing of HEK293 cells with the 13-DNR risk variant led to a 50% reduction of the CRMP2 isoform and twofold shortening of cellular projections. Transcriptome profiling of edited cells revealed schizophrenia-relevant expression signatures overlapping ZNF804A targets and antipsychotic drug responses ([PMID:27801893]).

Despite evidence of regulatory variant effects, the lack of reproducible association across multiple populations and absence of high-penetrance coding variants limit the genetic evidence to a ClinGen “Limited” level. Functional data reach a “Moderate” tier given concordant cellular and molecular assays. Additional rare variant, segregation, and animal model studies are required to advance the clinical validity.

Key Take-home: DPYSL2 regulatory variants modulate mTOR-dependent CRMP2 expression, suggesting a contributory, though currently limited, role in schizophrenia susceptibility.

References

• American Journal of Human Genetics • 2005 • Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. PMID:16380905
• Journal of human genetics • 2010 • A two-stage case-control association study of the dihydropyrimidinase-like 2 gene (DPYSL2) with schizophrenia in Japanese subjects. PMID:20414250
• The international journal of neuropsychopharmacology • 2006 • An investigation of the dihydropyrimidinase-like 2 (DPYSL2) gene in schizophrenia: genetic association study and expression analysis. PMID:16321170
• G3 (Bethesda, Md.) • 2014 • Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling. PMID:25416705
• Translational psychiatry • 2016 • The DPYSL2 gene connects mTOR and schizophrenia. PMID:27801893
• Translational psychiatry • 2020 • Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts. PMID:32873781

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