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Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?

ABSTRACT: Hundreds of variants in autosomal genes associated with the limb girdle muscular dystrophies (LGMDs) have been reported as being causative. However, in most cases the proof of pathogenicity derives from their non-occurrence in hundreds of healthy controls and/or from segregation studies in small families. The limited statistics of the genetic variations in the general population may hamper a correct interpretation of the effect of variants on the protein. To clarify the meaning of low-frequency variants in LGMD genes, we have selected all variants described as causative in the Leiden Open Variation Database and the Human Gene Mutation Database. We have systematically searched for their frequency in the NHLBI GO Exome Sequencing Project (ESP) and in our internal database. Surprisingly, the ESP contains about 4% of the variants previously associated with a dominant inheritance and about 9% of those associated with a recessive inheritance. The putative disease alleles are much more frequent than those estimated considering the disease prevalence. In conclusion, we hypothesize that a number of disease-associated variants are non-pathogenic and that other variations are not fully penetrant, even if they affect the protein function, suggesting a more complex genetic mechanisms for such heterogeneous disorders.

SUBMITTER: Di Fruscio G

PROVIDER: S-EPMC4519526 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?

Di Fruscio Giuseppina G Garofalo Arcomaria A Mutarelli Margherita M Savarese Marco M Nigro Vincenzo V

European journal of human genetics : EJHG 20150422 1

Hundreds of variants in autosomal genes associated with the limb girdle muscular dystrophies (LGMDs) have been reported as being causative. However, in most cases the proof of pathogenicity derives from their non-occurrence in hundreds of healthy controls and/or from segregation studies in small families. The limited statistics of the genetic variations in the general population may hamper a correct interpretation of the effect of variants on the protein. To clarify the meaning of low-frequency ...[more]

PMID: 25898921

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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.

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.

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Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?

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Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?

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