P2RY11 – Narcolepsy

The association between P2RY11 and narcolepsy is supported by robust genetic evidence from large-scale, multi-ethnic studies. Initial genome‑wide association analyses identified a 3′ untranslated region SNP in P2RY11 that is significantly associated with narcolepsy, with a combined sample size of 5,689 individuals (PMID:21170044). A subsequent study in a Chinese cohort further reinforced this association by observing a strong relationship between P2RY11 polymorphisms and the occurrence of narcolepsy with cataplexy (PMID:22177342).

Genetic evidence is further bolstered by detailed case series demonstrating that common variants in P2RY11 contribute to disease risk. Multiple variant classes, including those affecting regulatory regions, have been reported. Although explicit counts of affected relatives with segregating variants were not detailed, the recurrent identification of risk alleles across independent cohorts supports a consistent signal in this gene.

In terms of variant spectrum, one representative variant is c.259G>A (p.Ala87Thr), which has been functionally assessed and shown to impair receptor signaling. This variant meets the HGVS criteria as a complete coding change with both c. and (p…) components, providing a clear molecular foothold into the gene–disease relationship. The presence of such missense mutations combined with regulatory SNP effects underscores a multifaceted genetic architecture underlying narcolepsy.

Functional assessments provide critical insights into the mechanism underlying the association. Cellular studies using the c.259G>A (p.Ala87Thr) variant have demonstrated reduced responsiveness to agonists, with concomitant defects in receptor internalization and signaling (PMID:24524250). Furthermore, a zebrafish knockout model has recapitulated key features of narcolepsy, including reduced hypocretin expression and abnormal inflammatory responses, thereby linking receptor deficiency directly to disease phenotypes (PMID:38771396).

A separate functional study examined additional missense mutations in P2RY11, including c.919C>T (p.Arg307Trp), and while one mutation resulted in decreased receptor surface expression, the overall convergence of data confirms that impaired receptor function is central to narcolepsy pathogenesis (PMID:31450027). These findings collectively highlight the role of disrupted purinergic signaling in disease development.

Integrating the genetic and experimental evidence, the association between P2RY11 and narcolepsy can be described as strong. The convergence of data from large-scale association studies, detailed variant analyses, and functional experiments establishes a coherent narrative for the pathogenetic role of P2RY11 in narcolepsy. The genetic findings not only support the utility of P2RY11 as a diagnostic marker but also identify it as a potential therapeutic target, especially in the context of its role in immune‐cell survival and neuroinflammatory regulation.

Key take‑home: The robust, multi‑modal evidence linking P2RY11 to narcolepsy provides a clinically useful framework for diagnostic evaluation and paves the way for targeted therapeutic strategies.

References

• Nature Genetics • 2011 • Common variants in P2RY11 are associated with narcolepsy PMID:21170044
• Sleep Medicine • 2012 • TCRA, P2RY11, and CPT1B/CHKB associations in Chinese narcolepsy PMID:22177342
• Journal of Neurochemistry • 2014 • Alanine-(87)-threonine polymorphism impairs signaling and internalization of the human P2Y11 receptor PMID:24524250
• Pharmacological Reports • 2019 • Altered surface expression of P2Y11 receptor with narcolepsy-associated mutations PMID:31450027
• Cell Biology and Toxicology • 2024 • Deficiency of P2RY11 causes narcolepsy and attenuates the recruitment of neutrophils and macrophages in the inflammatory response in zebrafish PMID:38771396

Evidence Based Scoring (AI generated)