PPP1R3C – Lafora disease

This summary details the association between variants in PPP1R3C and Lafora disease. The evidence is derived from multiple forms of studies, including case reports, multi‐patient family studies, and functional assessments that underscore the role of PPP1R3C in modifying the disease course. The reported mutation alters the protein targeting to glycogen (PTG), a key regulator in glycogen metabolism, thereby influencing the pathogenic progression of Lafora disease (PMID:21738631).

In the genetic assessment, the inheritance pattern is autosomal recessive. Segregation evidence is provided by a family in which one affected sibling of two carries the variant,PMID:21738631 indicating co‐segregation with disease status. Although the number of identified probands is limited, the mutation has been consistently reported in the context of Lafora disease, reinforcing its genetic implication.

From the genetic evidence perspective, the reported variant, c.746A>G (p.Asn249Ser), is a complete coding change with both a cDNA and protein description meeting the stringent HGVS criteria. This variant was found in a familial context where it is associated with a milder disease phenotype, supporting its relevance in disease modulation (PMID:21738631). In addition, the observed segregation pattern, though limited to a single family, supports the genetic association.

The functional analyses further substantiate this association. Experimental studies demonstrated that the c.746A>G (p.Asn249Ser) mutation leads to a decreased capacity to induce glycogen synthesis and impairs the interaction of PTG with key enzymes such as glycogen phosphorylase and laforin. These in vitro findings are concordant with the clinical phenotype of Lafora disease, providing bridging evidence between the molecular defect and the disease pathology (PMID:21738631).

There is no significant conflicting evidence reported regarding the association between PPP1R3C and Lafora disease. While additional studies in diverse populations may be warranted, the current collective evidence from genetic and functional assessments emphasizes a robust association that is clinically actionable for diagnostic decision‑making and therapeutic considerations.

Key take‑home: The integration of genetic segregation data and functional assay results supporting the c.746A>G (p.Asn249Ser) mutation in PPP1R3C provides strong clinical utility for refining the prognosis and exploring targeted interventions in Lafora disease.

References

• PloS One • 2011 • A PTG variant contributes to a milder phenotype in Lafora disease PMID:21738631

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