L González-Mera1,2, G Ravenscroft3, M Cabrera-Serrano3,4,5,6, N Ermolova7, C Domínguez-González8, A Arteche-López9, P Soltanzadeh10, F Evesson11,12, C Navas1, F Mavillard5,6, J Clayton3, P Rodrigo1,2, E Servián-Morilla4,5,6, S T Cooper11,12,13, L Waddell11,13, K Reardon14, A Corbett15, A Hernandez-Laín16, A Sanchez17, J Esteban Perez8, C Paradas-Lopez4,5,6, E Rivas-Infante6,18, M Spencer19, N Laing3, M Olivé1,2. 1. Neuropathology Unit, Department of Pathology, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain. 2. Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain. 3. Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, WA, Australia. 4. Neurology Department, Hospital Universitario Virgen del Rocío, Seville, Spain. 5. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocıo/CSIC, Universidad de Sevilla, Sevilla, Spain. 6. Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. 7. Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 8. Neuromuscular Unit, Department of Neurology, Hospital Universitario 12 de Octubre, Research Institute imas12, Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 9. Department of Genetic, Hospital Universitario 12 de Octubre, Madrid, Spain. 10. Departments of Neurology and Physiology, David Geffen School of Medicine, UCLA, University of California, Los Angeles, CA, USA. 11. Kids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW, Australia. 12. The Children's Medical Research Institute, Westmead, NSW, Australia. 13. Discipline of Child and Adolescent Health, Faculty of Health and Medicine, University of Sydney, Westmead, NSW, Australia. 14. St. Vincent's Melbourne Neuromuscular Diagnostic Laboratory, Department of Clinical Neurosciences and Neurological Research, St Vincent's Hospital, Melbourne, VIC, Australia. 15. Department of Neurology, Concord General Repatriation Hospital, Sydney, NSW, Australia. 16. Department of Pathology, Neuropathology Unit. Hospital Universitario 12 de Octubre, Madrid, Spain. 17. Institut de Diagnòstic per la imatge (IDI), IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain. 18. Department of Neuropathology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain. 19. Department of Neurology, Neuromuscular Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Abstract
AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.
AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.
Authors: Francisco Diez-Fuertes; María Rosa López-Huertas; Javier García-Pérez; Esther Calonge; Mercedes Bermejo; Elena Mateos; Pilar Martí; Nuria Muelas; Juan Jesús Vílchez; Mayte Coiras; José Alcamí; Sara Rodríguez-Mora Journal: Front Cell Dev Biol Date: 2022-05-13
Authors: Clara Muñoz-Castro; Ayush Noori; Colin G Magdamo; Zhaozhi Li; Jordan D Marks; Matthew P Frosch; Sudeshna Das; Bradley T Hyman; Alberto Serrano-Pozo Journal: J Neuroinflammation Date: 2022-02-02 Impact factor: 8.322