Dataset Information

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

ABSTRACT: IMPORTANCE: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 MEASURE:Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. RESULTS:We 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

SUBMITTER: Rinaldi C

PROVIDER: S-EPMC5612424 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

Rinaldi Carlo C Schmidt Thomas T Situ Alan J AJ Johnson Janel O JO Lee Philip R PR Chen Ke-Lian KL Bott Laura C LC Fadó Rut R Harmison George H GH Parodi Sara S Grunseich Christopher C Renvoisé Benoît B Biesecker Leslie G LG De Michele Giuseppe G Santorelli Filippo M FM Filla Alessandro A Stevanin Giovanni G Dürr Alexandra A Brice Alexis A Casals Núria N Traynor Bryan J BJ Blackstone Craig C Ulmer Tobias S TS Fischbeck Kenneth H KH

JAMA neurology 20150501 5

<h4>Importance</h4>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.<h4>Objective</h4>To identify the genetic cause for a novel form of pure autosomal dominant HSP.<h4>Design, setting, and participants</h4>We examined and followed up with a family presenting to a tertiary referral center for eva ...[more]

PMID: 25751282

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Project description:BackgroundHereditary Spastic Paraplegia (HSP) represents a large group of clinically and genetically heterogeneous disorders linked to over 70 different loci and more than 60 recognized disease-causing genes. A heightened vulnerability to disruption of various cellular processes inherent to the unique function and morphology of corticospinal neurons may account, at least in part, for the genetic heterogeneity.MethodsWhole exome sequencing was utilized to identify candidate genetic variants in a four-generation Siberian kindred that includes nine individuals showing clinical features of HSP. Segregation of candidate variants within the family yielded a disease-associated mutation. Functional as well as in-silico structural analyses confirmed the selected candidate variant to be causative.ResultsNine known patients had young-adult onset of bilateral slowly progressive lower-limb spasticity, weakness and hyperreflexia progressing over two-to-three decades to wheel-chair dependency. In the advanced stage of the disease, some patients also had distal wasting of lower leg muscles, pes cavus, mildly decreased vibratory sense in the ankles, and urinary urgency along with electrophysiological evidence of a mild distal motor/sensory axonopathy. Molecular analyses uncovered a missense c.2155C > T, p.R719W mutation in the highly conserved GTP-effector domain of dynamin 2. The mutant DNM2 co-segregated with HSP and affected endocytosis when expressed in HeLa cells. In-silico modeling indicated that this HSP-associated dynamin 2 mutation is located in a highly conserved bundle-signaling element of the protein while dynamin 2 mutations associated with other disorders are located in the stalk and PH domains; p.R719W potentially disrupts dynamin 2 assembly.ConclusionThis is the first report linking a mutation in dynamin 2 to a HSP phenotype. Dynamin 2 mutations have previously been associated with other phenotypes including two forms of Charcot-Marie-Tooth neuropathy and centronuclear myopathy. These strikingly different pathogenic effects may depend on structural relationships the mutations disrupt. Awareness of this distinct association between HSP and c.2155C > T, p.R719W mutation will facilitate ascertainment of additional DNM2 HSP families and will direct future research toward better understanding of cell biological processes involved in these partly overlapping clinical syndromes.

Dataset Information

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

Publications

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

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