Mutation inCPT1CAssociated With Pure Autosomal Dominant Spastic Paraplegia

Abstract

The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.OBJECTIVE To identify the genetic cause for a novel form of pure autosomal dominant HSP. DESIGN, SETTING, AND PARTICIPANTS We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. MAIN OUTCOME AND MEASUREMutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. RESULTSWe identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) 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 on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c −/− mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.CONCLUSIONS AND RELEVANCE This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.

Carnitine palmitoyltransferase 1C: From cognition to cancer

“…A recent study by Rinaldi et al [90] This study also confirmed the expression of CPT1C in soma and dendritic and axonal projections of motor neurons, as well as its localization to the ER and not to mitochondria. A relevant finding from this study was the interaction between CPT1C…”

“…The findings that ceramide and sphingosine levels were reduced in brain motor regions of CPT1C KO mice [47] led the authors to propose this alteration as a potential cause of motor impairment in these animals. These deficits in CPT1C KO mice are consistent with the symptoms associated with human CPT1C mutation recently observed in hereditary spastic paraplegia, a human disorder affecting motor function [90].…”

“…Recently, a human CPT1C point-mutation in the N-terminal domain has been associated with spastic paraplegia [26]. Importantly, it is the first CPT1C mutationassociated pathology described in humans.…”

“…Recently, it has been demonstrated that CPT1C is expressed in mouse motor neurons and dorsal root ganglia, thereby indicating that it is also present in the peripheral nervous system [26] (Table 1).…”

“…An interesting potential new role for CPT1C in lipid metabolism has recently come to light, namely its involvement in lipid droplet (LD) synthesis [26]. LDs are the main organelles storing FAs in the form of TAG, the ER network being a major regulator in LD generation and expansion [43,44].…”