Novel CAPN3 variant associated with an autosomal dominant calpainopathy
- 28 April 2020
- journal article
- research article
- Published by Wiley in Neuropathology and Applied Neurobiology
- Vol. 46 (6), 564-578
- https://doi.org/10.1111/nan.12624
Abstract
Aims The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. Methods Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. Results We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. Conclusions We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in‐frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well‐documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re‐assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.Funding Information
- AFM-Téléthon (19272)
- Agence Nationale de la Recherche (ANR‐10‐INBS‐09)
- FP7 Coordination of Non-Community Research Programmes (NEUROMICS ‐ 2012–305121)
This publication has 40 references indexed in Scilit:
- Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21Muscle & Nerve, 2017
- A heterozygous 21-bp deletion inCAPN3causes dominantly inherited limb girdle muscular dystrophyBrain, 2016
- Genetic variability and clinical spectrum of Chinese patients with limb-girdle muscular dystrophy type 2AMuscle & Nerve, 2012
- Skeletal Muscle-specific Calpain Is an Intracellular Na+-dependent ProteaseOnline Journal of Public Health Informatics, 2010
- The clinical course of calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B)Neurological Research, 2010
- Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patientsHuman Mutation, 2007
- Calpain 3: a key regulator of the sarcomere?The FEBS Journal, 2006
- Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin–proteasome pathwayHuman Molecular Genetics, 2005
- Calpains and DiseaseThe New England Journal of Medicine, 2005
- Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2ACell, 1995