Novel splicing dysferlin mutation causing myopathy with intra-familial heterogeneity
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ORIGINAL ARTICLE
Novel splicing dysferlin mutation causing myopathy with intra‑familial heterogeneity Sabrine Rekik1,2 · Salma Sakka1 · Sawsan Ben Romdhane2 · Yasmine Baba Amer3 · Leila Lehkim4 · Nouha Farhat1 · Khaireddine Ben Mahfoudh5 · François Jérôme Authier3 · Mariem Dammak1 · Chokri Mhiri1,2 Received: 4 March 2020 / Accepted: 3 July 2020 © Springer Nature B.V. 2020
Abstract Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular disorders, caused by mutations in the dysferlin gene and characterized by a high degree of clinical variability even though within the same family. This study aims to describe three cases, belonging to a consanguineous Tunisian family, sharing a new splicing mutation in the dysferlin gene and presenting intra-familial variability of dysferlinopathies: Proximal–distal weakness and distal myopathy with anterior tibial onset. We performed the next generation sequencing for mutation screening and reverse transcriptase-PCR for gene expression analysis. Routine muscle histology was used for muscle biopsy processing. The clinical presentation demonstrated heterogeneous phenotypes between the three cases: Two presented intermediate phenotypes of dysferlinopathy with proximal–distal weakness and the third had a distal myopathy with anterior tibial onset. Genetic analysis yielded a homozygous splicing mutation (c.4597-2A>G) in the dysferlin gene, giving rise to the suppression of 28 bp of the exon 43. The splicing mutation found in our family (c.4597-2A>G) is responsible for the suppression of 28 bp of the exon 43 and a wide clinical intra-familial variability. Keywords Dysferlinopathies · DMAT · Proximal–distal weakness · DYSF and splicing mutation
Introduction Dysferlinopathies are a group of myopathies caused by mutations in the dysferlin gene (DYSF) [1]. DYSF is located on chromosome 2p13 and contains 55 coding exons spanning more than 150 kb [2]. The gene encodes a 230 kDa protein (DYSF), a member of the ferlin protein family with * Sabrine Rekik [email protected] 1
Laboratory of Neurogenetics, Parkinson’s Disease and Cerebrovascular Disease (LR‑12‑SP‑19), Habib Bourguiba University Hospital, University of Sfax, Sfax, Tunisia
2
Clinical Investigation Center (CIC), Habib Bourguiba University Hospital, Sfax, Tunisia
3
U955-IMRB, Team 10: Biology of the Neuromuscular System, Inserm, UPEC, Créteil, France
4
Pathology Laboratory, Habib Bourguiba University Hospital, Sfax, Tunisia
5
Radiology Department, Habib Bourguiba University Hospital, Sfax, Tunisia
seven C2 domains and repeated sequences termed DysfN and DysfC [3]. It plays a major role in the stability and integrity of the plasma membrane of the myocyte and the mechanism of the skeletal muscle repair [4, 5]. Dysferlin interacts also with caveolin 3 for T tubulogenesis, and with AHNAK for cell membrane differentiation and signal transduction [6]. DYSF is normally expressed at the level of the sarcolemma in skeletal muscle and is absent or reduced in patients with dysferlinopathies [7].
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