PLSCR5 and Bipolar Disorder

PLSCR5, a gene involved in the regulation of intracellular signaling, has recently been implicated in bipolar disorder. Recent genetic investigations have uncovered a very rare, heterozygous, and likely protein‐damaging variant in PLSCR5 that segregates with disease in a single family, suggesting a potential contributory role in the pathogenesis of bipolar disorder (PMID:24348429).

In the reported family, exome sequencing identified a heterozygous variant, c.123A>T (p.Lys41Asn), in PLSCR5 which was present in all three affected siblings and absent in the unaffected sibling. This observation indicates segregation of the variant with the bipolar phenotype, although the evidence is derived from a limited familial sample (PMID:24348429).

Genetically, the evidence comprises a single case report with segregation data supporting a pathogenic role for the PLSCR5 variant. The variant has been classified as rare and predicted to be protein‐damaging. Additionally, the study reported similar findings across a multi‐patient cohort; however, the identical study design limits the independent confirmation of this association.

The heterozygous state of the variant is consistent with an autosomal dominant mode of inheritance, with segregation analysis demonstrating that, besides the primary case, two additional affected relatives carry the variant. This pattern of inheritance supports the hypothesis of a dominant effect with potential incomplete penetrance.

Preliminary functional assessments have indicated that disruption of PLSCR5 may interfere with CREB-regulated intracellular signaling pathways, which are crucial for neuronal plasticity and mood regulation. Although these functional insights lend biological plausibility to the genetic findings, further experimental validation is required to fully establish the mechanism of pathogenicity.

In summary, the cumulative evidence supports a limited association between PLSCR5 and bipolar disorder. While the genetic data from a single family and initial functional studies provide an intriguing link, additional independent studies are necessary before this association can be clinically implemented. Key take‑home sentence: Integrating rare, heterozygous variants in PLSCR5 with preliminary functional disruption of intracellular signaling offers a promising target for further research in the diagnostic and therapeutic landscape of bipolar disorder.

References

• Frontiers in Psychiatry • 2013 • Rare Genomic Variants Link Bipolar Disorder with Anxiety Disorders to CREB-Regulated Intracellular Signaling Pathways PMID:24348429

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