2. Academic Validation
  3. Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia

  • JAMA Neurol. 2015 May;72(5):561-70. doi: 10.1001/jamaneurol.2014.4769.
Carlo Rinaldi 1,  Thomas Schmidt 2,  Alan J Situ 2,  Janel O Johnson 3,  Philip R Lee 4,  Ke-Lian Chen 1,  Laura C Bott 5,  Rut Fadó 6,  George H Harmison 1,  Sara Parodi 7,  Christopher Grunseich 1,  Benoît Renvoisé 1,  Leslie G Biesecker 8,  Giuseppe De Michele 9,  Filippo M Santorelli 10,  Alessandro Filla 9,  Giovanni Stevanin 11,  Alexandra Dürr 12,  Alexis Brice 12,  Núria Casals 6,  Bryan J Traynor 3,  Craig Blackstone 1,  Tobias S Ulmer 2,  Kenneth H Fischbeck 1
Affiliations

Affiliations

  • 1 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
  • 2 Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.
  • 3 Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
  • 4 Section on Nervous System Development and Plasticity, The Eunice Kennedy Shriver National Institute of Child and Human Development, National Institutes of Health, Bethesda, Maryland.
  • 5 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland5Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 6 Basic Sciences Department, Facultat de Medicina i Ciències de la Salut, Universitat Internacional de Catalunya, and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Sant Cugat del Vallés, Spain.
  • 7 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland7Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
  • 8 Genetic Disease Research Branch, National Human Genome Research Institute, and the National Institutes of Health Intramural Sequencing Center, National Institutes of Health, Bethesda, Maryland.
  • 9 Department of Neurosciences, Reproductive Sciences, and Odontostomatology, University of Naples Federico II, Naples, Italy.
  • 10 Neurogenetics Istituto di Ricovero e Cura a Carattere Scientifico, Stella Maris, Pisa, Italy.
  • 11 Institut du Cerveau et de la Moelle Épinière, Paris, France12Laboratoire de Neurogénétique, École Pratique des Hautes Études-héSam Université, Institut du Cerveau et de la Moelle Épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France13Sorbonne Univ.
  • 12 Institut du Cerveau et de la Moelle Épinière, Paris, France13Sorbonne Universités, Université Pierre et Marie Curie, Institut du Cerveau et de la Moelle Épinière, Paris, France14Department of Genetics, Assistance Publique Hopitaux de Paris, Groupe Hospita.
PMID: 25751282 DOI: 10.1001/jamaneurol.2014.4769
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 < .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.

Figures