Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia

Am J Hum Genet. 2016 May 5;98(5):1038-1046. doi: 10.1016/j.ajhg.2016.04.002.

Ziv Gan-Or ¹, Naima Bouslam ², Nazha Birouk ³, Alexandra Lissouba ⁴, Daniel B Chambers ⁵, Julie Vérièpe ⁴, Alaura Androschuk ⁵, Sandra B Laurent ⁶, Daniel Rochefort ⁶, Dan Spiegelman ⁶, Alexandre Dionne-Laporte ⁶, Anna Szuto ⁷, Meijiang Liao ⁴, Denise A Figlewicz ⁸, Ahmed Bouhouche ², Ali Benomar ², Mohamed Yahyaoui ², Reda Ouazzani ³, Grace Yoon ⁹, Nicolas Dupré ¹⁰, Oksana Suchowersky ¹¹, Francois V Bolduc ⁵, J Alex Parker ¹², Patrick A Dion ⁶, Pierre Drapeau ⁴, Guy A Rouleau ¹³, Bouchra Ouled Amar Bencheikh ¹⁴

Affiliations

1 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada.
2 Equipe de Recherche sur les Maladies Neurodégénératives, Medical School and Pharmacy, Mohammed V University, Rabat, BP 6527, Morocco.
3 Service de Neurophysiologie Clinique, Hôpital des Spécialités, Centre Hospitalier Ibn Sina, Université Mohammed V Souissi, Rabat, BP 6527, Morocco.
4 Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
5 Department of Pediatrics, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada.
6 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada.
7 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
8 Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
9 Division of Neurology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
10 Division of Neurology, Centre Hospitalier Universitaire de Québec, and Faculty of Medicine, Laval University, Quebec City, QC G1V 0A6, Canada.
11 Division of Neurology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
12 Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de Neurosciences, Université de Montréal, Montréal, QC H3C 3J7, Canada.
13 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada. Electronic address: guy.rouleau@mcgill.ca.
14 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada.

PMID: 27153400 DOI: 10.1016/j.ajhg.2016.04.002

Abstract

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome Sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and Sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a Protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.

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