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In a single familial study, the PSEN1 M146L variant (c.436A>C (p.Met146Leu)) was identified in multiple affected members of one kindred presenting with Pick bodies pathology without classic Alzheimer features. This variant co-segregated with frontotemporal tauopathy, but only one pedigree has been reported and the exact number of informative meioses is limited (PMID:15622541).
Functional analysis of brain tissue from M146L carriers revealed Sarkosyl-insoluble, hyperphosphorylated tau predominantly comprising three-repeat isoforms, implicating dysregulated tau phosphorylation and amyloid metabolism in Pick disease pathogenesis (PMID:15622541). Together, these data support a limited gene–disease association for PSEN1 in Pick disease based on a single pedigree and concordant neuropathology. Additional familial and mechanistic studies are required to confirm this link. Key take-home: PSEN1 M146L should be considered in the diagnostic evaluation of familial tauopathies with Pick body pathology, but clinical utility is constrained by limited evidence.
Gene–Disease AssociationLimitedSingle family with PSEN1 M146L variant showing Pick body pathology without replication or extensive segregation data ([PMID:15622541]). Genetic EvidenceLimitedOne PSEN1 missense variant (c.436A>C (p.Met146Leu)) identified in a single pedigree, with insufficient segregation and no additional case series ([PMID:15622541]). Functional EvidenceLimitedBrain tissue from M146L carriers exhibited Sarkosyl-insoluble hyperphosphorylated tau with three-repeat isoforms, consistent with Pick pathology but derived from one study ([PMID:15622541]). |