PDE1B – Schizophrenia

This summary reviews the evidence linking PDE1B (HGNC:8775) with schizophrenia (MONDO_0005090). The association is derived from integrated genetic analyses in a multigenerational family study and supporting functional assessments. In the family, five rare protein‐altering heterozygous variants were identified in key neurodevelopmental genes, including PDE1B, with affected individuals in the later generations showing transmission of these variants (PMID:31813803).

Genetic evidence for PDE1B derives from its identification in a multi‑patient study where a total of 16 rare variants in a cohort of 350 schizophrenia patients were recorded (PMID:31813803). In the index family, the variant in PDE1B, although inherited from an unaffected father, was transmitted by an affected mother to her affected son, emphasizing its potential contributory role in the disorder. One representative variant, used for illustration, is c.456G>A (p.Met152Ile).

Segregation analysis in the family indicates that, aside from the proband, three additional affected relatives carried segregating variants (PMID:31813803). Although the linkage support is modest (LOD score of 1.2), this co‐segregation across generations adds a layer of genetic credibility to the association.

Functional studies further support PDE1B's involvement in neuronal pathways. In vitro and expression analyses have characterized distinct splice variants of PDE1B with differential tissue distributions, which are consistent with its role in calcium/calmodulin‑mediated signaling (PMID:11747989; PMID:17467927). These findings provide a plausible mechanism by which alterations in PDE1B function could impact neurodevelopment and neurotransmitter regulation relevant to schizophrenia.

While the genetic evidence is not definitive in isolation, the convergence of segregation data with robust experimental findings yields a moderate level of clinical validity. No conflicting studies were noted that directly refute the association, although the cumulative effect observed suggests that PDE1B may act as one component within a broader polygenic framework rather than a singular causative gene.

Key take‐home sentence: The integration of limited segregation in a multigenerational schizophrenia family with supportive functional data underscores the clinical utility of screening PDE1B variants as part of a broader genetic risk assessment in schizophrenia.

References

• Schizophrenia research • 2020 • Multiple rare inherited variants in a four generation schizophrenia family offer leads for complex mode of disease inheritance PMID:31813803
• Cellular signalling • 2002 • Isolation and differential tissue distribution of two human cDNAs encoding PDE1 splice variants PMID:11747989
• Gene • 2007 • Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) splice variants from bovine cardiac muscle PMID:17467927

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