Novel splicing dysferlin mutation causing myopathy with intra-familial heterogeneity

• Published in: Molecular biology reports Vol. 47; no. 8; pp. 5755 - 5761
• Main Authors: Rekik, Sabrine, Sakka, Salma, Romdhane, Sawsan Ben, Amer, Yasmine Baba, Lehkim, Leila, Farhat, Nouha, Mahfoudh, Khaireddine Ben, Authier, François Jérôme, Dammak, Mariem, Mhiri, Chokri
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.08.2020; Springer Nature B.V
• Subjects: Animal Anatomy; Animal Biochemistry; Biomedical and Life Sciences; Biopsy; Dysferlin - genetics; Female; Gene expression; Genetic analysis; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing - methods; Histology; Humans; Life Sciences; Male; Middle Aged; Morphology; Muscular Diseases - genetics; Muscular Diseases - pathology; Muscular Dystrophies, Limb-Girdle - genetics; Muscular Dystrophies, Limb-Girdle - pathology; Mutation; Myopathy; Next-generation sequencing; Original Article; Phenotype; Phenotypes; RNA Splicing; RNA-directed DNA polymerase; Splicing; DYSF and splicing mutation; Dysferlinopathies; Proximal–distal weakness; DMAT
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-020-05643-9

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.