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Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by progressive lower limb spasticity and weakness ([HP:0001257]). Through whole‐exome sequencing of a three‐generation kindred, a heterozygous c.109C>T (p.Arg37Cys) variant in CPT1C was identified, cosegregating with pure autosomal dominant HSP in five affected individuals (PMID:25751282).
This c.109C>T (p.Arg37Cys) variant was absent from public single‐nucleotide polymorphism databases and 712 control exomes, and was confirmed by Sanger sequencing in all affected and excluded from unaffected family members (PMID:25751282). In a Yunnan cohort of 11 HSP patients, the reported CPT1C SNP rs150853576 was observed in ten individuals (PMID:35282124), while two pediatric HSP patients harbored other CPT1C variants (PMID:36109173), suggesting recurrent involvement but without clear segregation in these series.
Biochemical assays using nuclear magnetic resonance spectroscopy demonstrated that p.Arg37Cys alters CPT1C conformation and reduces both the number (213.0 ± 46.99 vs 81.9 ± 14.2; P < .01) and size (0.29 ± 0.01 vs 0.26 ± 0.01; P < .05) of lipid droplets in transfected cells, supporting a dominant‐negative effect (PMID:25751282).
In primary cortical neurons from Cpt1c−/− mice, lipid droplet counts were significantly reduced relative to wild-type (1.0 ± 0.12 vs 0.44 ± 0.05; P < .001), paralleling cellular findings and reinforcing a loss of function with dominant interference mechanism (PMID:25751282).
Overall, genetic evidence comprises a single family with cosegregation of a deleterious variant, augmented by limited independent observations, while concordant in vitro and in vivo models delineate a dominant‐negative mechanism. Further large‐scale studies are needed to delineate variant spectrum and penetrance.
Key take-home: CPT1C variants, exemplified by p.Arg37Cys, are implicated in autosomal dominant HSP through a dominant‐negative mechanism disrupting lipid droplet biogenesis and provide a potential diagnostic target.
Gene–Disease AssociationLimitedOne family with a segregating c.109C>T (p.Arg37Cys) in five affected individuals ([PMID:25751282]); limited additional case observations Genetic EvidenceLimitedCosegregation of one variant in a single family of five ([PMID:25751282]); limited series in ten and two additional unsegregated cases ([PMID:35282124], [PMID:36109173]) Functional EvidenceModerateIn vitro and mouse model studies demonstrate induced conformational change, lipid droplet reduction, and dominant-negative effect ([PMID:25751282]) |