Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
JAMA Neurol. 2015-05-01; 72(5): 561
DOI: 10.1001/jamaneurol.2014.4769
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1. JAMA Neurol. 2015 May;72(5):561-70. doi: 10.1001/jamaneurol.2014.4769.
Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
Rinaldi C(1), Schmidt T(2), Situ AJ(2), Johnson JO(3), Lee PR(4), Chen KL(1),
Bott LC(5), Fadó R(6), Harmison GH(1), Parodi S(7), Grunseich C(1), Renvoisé
B(1), Biesecker LG(8), De Michele G(9), Santorelli FM(10), Filla A(9), Stevanin
G(11), Dürr A(12), Brice A(12), Casals N(6), Traynor BJ(3), Blackstone C(1),
Ulmer TS(2), Fischbeck KH(1).
Author information:
(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.
Erratum in
JAMA Neurol. 2015 May;72(5):608.
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