Dysferlinopathy in the Jews of the Caucasus: A frequent mutation in the dysferlin gene
Introduction
Limb Girdle Muscular Dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM) and distal anterior compartment myopathy are autosomal recessive muscular disorders caused by mutations in the dysferlin gene (DYSF) [1], [2]. Dysferlin deficiency is demonstrated in muscle biopsy by immunohistochemistry and immunoblotting. The DYSF gene is located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA [3], [4]. The transcript is 6.3 kb large and is mainly expressed in skeletal muscle and heart [5]. The protein is involved in calcium dependent membrane fusion step of the muscle fiber repair process [6], [7]. No hot spot has been identified, and missense, nonsense and frameshift mutations have all been reported (Leiden Muscular Dystrophy database http://www.dmd.nl). About 400 allelic variants were described, 70% base substitutions and 20% small deletions consequently mutation analysis of DYSF remains a time-consuming task. Three ethnic clusters have been reported in LGMD2B: Libyan Jews [1], [8], Italian [9] and Spanish [10] populations with a clear founder effect. In the Libyan Jews there is only a single DYSF mutation while in the Italy and Spain other mutations were found.
We have lately noticed another potential ethnic cluster of Dysferlinopathy in the Israel among Jews originating from the Caucasus Mountains region. Jews from the area bordered on the south by Anatolia and Iran in Asia, on the west by the Black Sea, on the east by the Caspian Sea and on the north by Russia belong to a highly inbred community, thus we assumed a founder effect and a common mutation in Dysferlinopathy patients originating from this geographical area.
The aim of this study was to perform a genomic analysis of the dysferlin coding sequence in this community.
Section snippets
Patients
Ten patients from eight families originating from the Caucasus affected by muscular dystrophy were examined by neurologists from four Medical Centers in Israel. An informed consent was obtained from all patients, as well as from the healthy individuals. In three families, various degrees of consanguinity were established. At least one subject in every family had a muscle biopsy that confirmed the diagnosis of Dysferlinopathy. All patients had serum CK measurements and had had an EMG study at
Western blot analysis
Western blot analysis revealed a complete absence of the dysferlin signal while merosin (as a reference protein) was normal. Fig. 1 shows a representing three patients from the Caucasus with LGMD2B.
Genomic sequencing
Genetic analysis was first performed on the entire coding region and intron/exon boundaries of the DYSF gene in one patient. A single G base deletion at codon 927 (c.2779, exon 26) was found in a homozygous status, the parents being carriers (Fig. 2). The mutation was confirmed by a mismatch PCR
Discussion
We describe here a common mutation in Dysferlinopathy Jewish patients originating from Caucasus region. This mutation (2779delG) in exon 26 (codon 927) causes a frameshift in translation resulting in a downstream termination and consequently a truncated protein. The total absence of dysferlin protein analyzed by Western blot in our patients is well understood since antibodies used for dysferlin detection are aimed at amino acids 1999–2016 of the dysferlin, which are predicted to be absent in
References (15)
- et al.
Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing
J Biol Chem
(2003) - et al.
A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B
Nat Genet
(1998) - et al.
Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy
Nat Genet
(1998) - et al.
Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12–14
Neurology
(1995) - et al.
Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy
Neurology
(2001) - et al.
Dysferlin is a plasma membrane protein and is expressed early in human development
Hum Mol Genet
(1999) - et al.
Defective membrane repair in dysferlin-deficient muscular dystrophy
Nature
(2003)
Cited by (34)
Genetic cause of heterogeneous inherited myopathies in a cohort of Greek patients
2020, Molecular Genetics and Metabolism ReportsNeuromuscular disorders in Israel: A model country for ethnic clusters
2019, Neuromuscular DisordersCitation Excerpt :Milder forms were also identified within this community making the issue of genotype-phenotype correlation of lesser importance in this group, since they all are homozygous for the same founder mutation. Interestingly, in an even smaller Jewish community which was very isolated through history in the Caucasus mountain area, another founder mutation (2779delG) was found in 2007 with an estimated carrier rate of 4% [4]. The dysferlin story in Libyan Jews is typical for a recessively-inherited myopathy in a closed, well-defined small community.
Where do we stand in trial readiness for autosomal recessive limb girdle muscular dystrophies?
2016, Neuromuscular DisordersDysferlinopathy in Iran: Clinical and genetic report
2015, Journal of the Neurological SciencesCitation Excerpt :In our patients, clinically the weakest proximal muscles were the iliopsoas, quadriceps and hamstrings and at advanced stages, the feet and toes dorsiflexors were usually weaker than the gastrocnemius. Our findings are similar to Leshinsky-Silver et al. study who described 10 patients from 8 families originating from the Caucasus affected by dysferlinopathy [13]. In another report from China, 43 different disease-causing mutations (including 31 novel ones) have been identified in 34 patients [18].
A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing
2015, Neuromuscular DisordersCitation Excerpt :In our patients, there was not a single identical mutation found in DYSF gene. No one had the founder mutations identified in the Western patients [19,20]. The phenotypes of dysferlinopathy patients were diverse.
McArdle disease: A novel mutation in Jewish families from the Caucasus region
2012, Molecular Genetics and MetabolismCitation Excerpt :The c.632delG (p.S211T-294X) mutation was initially identified in patient 1 by sequence analysis of all 20 exons of the PYGM gene. Given that Jews of the Caucasus (also called Mountain Jews) are distinct ethnic group that are highly inbreeded [8] and in view of the similar clinical and laboratory findings, when patients 2 and 3 presented later we searched directly for the same mutation. Molecular analysis was preferred for confirmation over the myophosphorylase assay because it does not require an invasive procedure and has advantages in terms of genetic consults.