Dataset Information

Causative variants linked with limb girdle muscular dystrophy in an Iranian population: 6 novel variants.

ABSTRACT:

Background

Limb-girdle muscular dystrophy (LGMD) is a non-syndromic muscular dystrophy caused by variations in the genes involved in muscle structure, function and repair. The heterogeneity in the severity, progression, age of onset, and causative genes makes next-generation sequencing (NGS) a necessary approach for the proper diagnosis of LGMD.

Methods

In this article, 26 Iranian patients with LGMD criteria were diagnosed with disease variants in the genes encoding calpain3, dysferlin, sarcoglycans and Laminin α-2. Patients were referred to the hospital with variable distribution of muscle wasting and progressive weakness in the body. The symptoms along with biochemical and EMG tests were suggestive of LGMD; thus the genomic DNA of patients were investigated by whole-exome sequencing including flanking intronic regions. The target genes were explored for the disease-causing variants. Moreover, the consequence of the amino acid alterations on proteins' secondary structure and function was investigated for a better understanding of the pathogenicity of variants. Variants were sorted based on the genomic region, type and clinical significance.

Results

In a comprehensive investigation of previous clinical records, 6 variations were determined as novel, including c.1354-2 A > T and c.3169_3172dupCGGC in DYSF, c.568 G > T in SGCD, c.7243 C > T, c.8662_8663 insT and c. 4397G > C in LAMA2. Some of the detected variants were located in functional domains and/or near to the post-translational modification sites, altering or removing highly conserved regions of amino acid sequence.

SUBMITTER: Mianesaz H

PROVIDER: S-EPMC9938754 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Causative variants linked with limb girdle muscular dystrophy in an Iranian population: 6 novel variants.

Mianesaz Hamidreza H Ghalamkari Safoura S Salehi Mansoor M Behnam Mahdiyeh M Hosseinzadeh Majid M Basiri Keivan K Ghasemi Majid M Sedghi Maryam M Ansari Behnaz B

Molecular genetics & genomic medicine 20221114 2

<h4>Background</h4>Limb-girdle muscular dystrophy (LGMD) is a non-syndromic muscular dystrophy caused by variations in the genes involved in muscle structure, function and repair. The heterogeneity in the severity, progression, age of onset, and causative genes makes next-generation sequencing (NGS) a necessary approach for the proper diagnosis of LGMD.<h4>Methods</h4>In this article, 26 Iranian patients with LGMD criteria were diagnosed with disease variants in the genes encoding calpain3, dysf ...[more]

PMID: 36374152

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Project description:ObjectiveTo identify novel biomarkers as an alternative diagnostic tool for limb girdle muscular dystrophy (LGMD).BackgroundLGMD encompasses a group of muscular dystrophies characterized by proximal muscles weakness, elevated CK levels and dystrophic findings on muscle biopsy. Heterozygous CAPN3 mutations are associated with autosomal dominant LGMD-4, while biallelic mutations can cause autosomal recessive LGMD-1. Diagnosis is currently often based on invasive methods requiring muscle biopsy or blood tests. In most cases Western blotting (WB) analysis from muscle biopsy is essential for a diagnosis, as muscle samples are currently the only known tissues to express the full-length CAPN3 isoform.MethodsWe analyzed CAPN3 in a cohort including 60 LGMD patients. Selected patients underwent a complete neurological examination, electromyography, muscle biopsy, and skin biopsies for primary fibroblasts isolation. The amount of CAPN3 was evaluated by WB analysis in muscle and skin tissues. The total RNA isolated from muscle, fibroblast and urine was processed, and cDNA was used for qualitative analysis. The expression of CAPN3 was investigated by qRT-PCR. The CAPN3 3D structure has been visualized and analyzed using PyMOL.ResultsAmong our patients, seven different CAPN3 mutations were detected, of which two were novel. After sequencing CAPN3 transcripts from fibroblast and urine, we detected different CAPN3 isoforms surprisingly including the full-length transcript. We found comparable protein levels from fibroblasts and muscle tissue; in particular, patients harboring a novel CAPN3 mutation showed a 30% reduction in protein compared to controls from both tissues.ConclusionsOur findings showed for the first time the presence of the CAPN3 full-length transcript in urine and skin samples. Moreover, we demonstrated surprisingly comparable CAPN3 protein levels between muscle and skin samples, thus allowing us to hypothesize the use of skin biopsy and probably of urine samples as an alternative less invasive method to assess the amount of CAPN3 when molecular diagnosis turns out to be inconclusive.

Project description:BackgroundThe POMT2 gene, which encodes protein O-mannosyltransferase 2, is essential for α-dystroglycan glycosylation. Variants in POMT2 cause various disorders, including the relatively rare presentation of limb-girdle muscular dystrophy R14 (LGMDR14).MethodsThis study retrospectively analyzed the clinical, pathological, and genetic data of three LGMDR14 patients. And we investigated the pathogenic mechanisms of POMT2 variants through aberrant mRNA processing analysis and molecular dynamics simulations to assess their impact on protein structure and function.ResultsWe recruited three LGMDR14 patients from unrelated Chinese families, all presenting with adult-onset proximal muscle weakness. All of these patients showed a myopathic pattern on electromyography and decreased α-dystroglycan expression on muscle biopsy. One patient had severe cardiomyopathy and mild cognitive impairment. Genetic sequencing revealed compound heterozygous variants in the POMT2 gene in all three patients: c.1006 + 1G > A and c.295 C > T in patient 1, c.1261 C > T and c.700_701insCT in patient 2, and c.812 C > T and c.170G > A in patient 3. Variants c.700_701insCT, c.812 C > T, and c.170G > A are novel. Splicing and cDNA analysis revealed that the c.1006 + 1G > A variant could cause retention of the first 26 bp of intron 8 by inducing recognition of new donor splice sites. Pyrosequencing revealed that both frameshift variant c.700_701insCT and splicing variant c.1006 + 1G > A triggered a nonsense-mediated mRNA decay. Molecular dynamics indicated that c.1006 + 1G > A, c.700_701insCT, and c.170G > A variants could lead to truncated proteins, altering stability and function.ConclusionsOur study summarizes the clinical, pathological and genetic characteristics of three adult-onset LGMDR14 patients, expanding the genetic spectrum of POMT2 variants. Moreover, the finding reinforces the impact of POMT2 splicing defects on mRNA regulation, and molecular dynamics simulations predict the structural consequences of POMT2 variants, providing additional evidence for their functional effects.

Dataset Information

Causative variants linked with limb girdle muscular dystrophy in an Iranian population: 6 novel variants.

Background

Methods

Results

Publications

Causative variants linked with limb girdle muscular dystrophy in an Iranian population: 6 novel variants.

Similar Datasets

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