Digenic Variants in the TTN and TRAPPC11 Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family.
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SUBMITTER: Chen Q
PROVIDER: S-EPMC7969792 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
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Digenic Variants in the <i>TTN</i> and <i>TRAPPC11</i> Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family.
Chen Qian Q Zheng Wen W Xu Hongbo H Yang Yan Y Song Zhi Z Yuan Lamei L Deng Hao H
Frontiers in neuroscience 20210304
Limb-girdle muscular dystrophies (LGMD) are hereditary genetic disorders characterized by progressive muscle impairment which predominantly include proximal muscle weaknesses in the pelvic and shoulder girdles. This article describes an attempt to identify genetic cause(s) for a LGMD pedigree via a combination of whole exome sequencing and Sanger sequencing. Digenic variants, the titin gene (<i>TTN</i>) c.19481T>G (p.Leu6494Arg) and the trafficking protein particle complex 11 gene (<i>TRAPPC11</ ...[more]
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Project description:Limb girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic myopathies leading primarily to proximal muscle weakness. It is caused by mutations at over 50 known genetic loci typically from mutations in genes encoding constituents of the sarcolemmal dystrophin complex or related functions. Herein we describe the case of two siblings with LGMD that were investigated using whole-exome sequencing followed by Sanger sequencing validation of a specific double-mutation in the TRAPPC11 gene. Further, from parental sequencing we determined the mode of transmission, a double heterozygous mutation at the maternal and paternal alleles. The two mutations detected have not been described in other patients.
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Project description:We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (rs143445685), CAPN3 (rs138172448), and DES (rs144901249) genes. We hypothesized that the inheritance pattern could follow a digenic pattern of inheritance. Screening for these polymorphisms in an unaffected sister revealed the presence of all these same variants except for that in the CAPN3 gene. All variants were studied to determine their frequency and if they had been previously reported as mutations. They were also subjected to protein modeling programs, including SIFT, PolyPhen, and MutationTaster. This analysis indicated that the CAPN3 variant c.1663G>A (rs138172448), which results in a p.Val555Ile change, and the DES gene variant c.656C>T (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the CAPN3 and DES genes, through digenic inheritance, are the cause of the myopathy in this patient.
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Project description:BackgroundLimb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible.AimThis study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10.MethodsDNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing.ResultsWhole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10.ConclusionWe identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.
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Project description:Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.
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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.
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Project description:Limb-girdle muscular dystrophies (LGMDs) are a group of neuromuscular diseases that are characterized by progressive muscle weakness. LGMD type 2A (LGMD2A), caused by variants in the calpain-3 (CAPN3) gene, is the most prevalent type. The present study aimed to analyze pathogenic CAPN3 gene variants in two pedigrees affected by LGMD2A. Each family contains three patients who are siblings and sought genetic counseling. Genomic DNA was extracted from the peripheral blood samples collected from the probands and family members and whole-exome sequencing (WES) was used to detect the pathogenic genes in the probands. Suspected variants were subsequently validated by Sanger sequencing. In family 1, WES revealed that the proband carried the compound heterogeneous variants c.1194-9A>G and c.1437C>T (p.Ser479=) in CAPN3 (NM_000070.2). In family 2, WES identified that the proband carried the compound heterogeneous variants c.632+4A>G and c.1468C>T (p.Arg490Trp) in CAPN3 (NM_000070.2). In conclusion, the present study indicated that the compound heterogeneous variants of the CAPN3 gene were most likely responsible for LGMD2A in the two Chinese families.
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Project description:Limb-girdle muscular dystrophy (LGMD) is a group of muscular dystrophies with predominantly proximal muscular weakness, and some genes associated with this disease have been identified at present. LGMD type 2Q (LGMD2Q) is a subtype of LGMD and is associated with PLEC gene mutation. Major phenotypes of PLEC gene mutation include epidermolysis bullosa with late-onset muscular dystrophy and epidermolysis bullosa with other lesions. LGMD2Q without skin lesions is rarely reported. This article reviews the pathogenic gene PLEC and clinical manifestations of LGMD2Q, so as to deepen the understanding of the pathogenic gene and phenotype of LGMD2Q.
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