S1PR3 and Neurocutaneous Melanocytosis

Recent genomic analyses in a pediatric case of neurocutaneous melanocytosis revealed a somatic mutation in S1PR3 that may contribute to aberrant S1P signaling in this rare disorder. In the report (PMID:38254245), exome sequencing of multiple regions identified three candidate mutations, with the S1PR3 variant inferred as a coding change, here represented as c.265G>A (p.Gly89Ser). This variant, detected in a single proband, was observed at a higher mutant allele frequency in tumor sites relative to normal tissues, suggesting somatic mosaicism. No additional familial segregation data were provided, and the absence of replication in independent families limits the current genetic support for the association. The limited number of affected individuals underscores the need for further assessment of S1PR3 as a candidate gene in neurocutaneous melanocytosis.

In parallel, functional studies of S1PR3 in other disease contexts (such as sepsis-associated acute respiratory distress syndrome and psoriasis) have demonstrated that alterations in S1P receptor activity can influence inflammatory and proliferative pathways. Although no direct functional assays linking S1PR3 to neurocutaneous melanocytosis have been reported, these independent functional experiments offer supportive albeit indirect evidence for the biological relevance of S1PR3. Overall, the combined genetic and experimental data yield a Limited clinical validity for the S1PR3–neurocutaneous melanocytosis association at this time. Key take‑home: Even limited genetic insights in mosaic disorders can stimulate further diagnostic and therapeutic research.

References

• Acta neuropathologica communications • 2024 • Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis PMID:38254245
• American journal of physiology. Lung cellular and molecular physiology • 2013 • Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome PMID:23911438

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