Truncating variant in MYOF gene is associated with limb-girdle type muscular dystrophy and cardiomyopathy
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ABSTRACT:
PROVIDER: PRJNA487792 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7752726.fastq.gz | Fastqsanger.gz | |||
| SRR7752727.fastq.gz | Fastqsanger.gz | |||
| SRR7752728.fastq.gz | Fastqsanger.gz | |||
| SRR7752729.fastq.gz | Fastqsanger.gz |
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Project description:Even though genetic studies of individuals with neuromuscular diseases have uncovered the molecular background of many cardiac disorders such as cardiomyopathies and inherited arrhythmic syndromes, the genetic cause of a proportion of cardiomyopathies associated with neuromuscular phenotype still remains unknown. Here, we present a clinical case with a combination of cardiomyopathy and limb-girdle type muscular dystrophy where whole exome sequencing identified myoferlin (MYOF) - a member of the Ferlin protein family and close homolog of DYSF - as the most likely candidate gene. The disease-causative role of the identified variant c.[2576delG; 2575G>C], p.G859fs is supported by functional studies in vitro using primary patient's satellite cells, including both RNA sequencing and morphological studies, as well as recapitulating of muscle phenotype in vivo in zebrafish experiments. We provide the first evidence supporting a role of MYOF in human muscle disease.
2019-08-24 | GSE119027 | GEO
Project description:26 limb-girdle muscular dystrophy patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 204 healthy unrelated controls were genotyped for 96 most frequent known limb-girdle muscular dystrophies causing mutations for the region, using VeraCode GoldenGate system. More information can be found in article Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies in BMC Musculoskeletal Disorders by I. Inashkina et al.
2016-04-28 | E-MTAB-4662 | biostudies-arrayexpress
Project description:Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients’ muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.
2024-02-29 | GSE253519 | GEO
Project description:Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features
| PRJNA1065958 | ENA
Project description:Introduction: Reported frequencies of cardiomyopathy in limb girdle muscular dystrophy R9 (LGMDR9) vary. We describe the frequency and age at onset of cardiomyopathy in an LDMDR9 cohort.Methods: Echocardiograms from 56 subjects (157 echocardiograms) with LGMDR9 were retrospectively reviewed. The cumulative probability of having an abnormal echocardiogram as a function of age was assessed by survival analysis for interval-censored data by genotype. Correlations between cardiac and clinical function were evaluated.Results: Twenty-five (45%) participants had cardiomyopathy. The median age at first abnormal echocardiogram for subjects homozygous for the c.826C>A variant was 54.2 y compared to 18.1 y for all other fukutin-related protein (FKRP) genotypes (P <?.0001). There was a weak correlation between ejection fraction and 10-Meter Walk Test speed (r = 0.25), but no correlation with forced vital capacity (r = 0.08).Discussion: Cardiomyopathy is prevalent among those with LGMDR9 and occurs later in subjects homozygous for the c.826C>A mutation. These data will help to guide surveillance and management.
| S-EPMC7693230 | biostudies-literature
Project description:Even though genetic studies of individuals with neuromuscular diseases have uncovered the molecular background of many cardiac disorders such as cardiomyopathies and inherited arrhythmic syndromes, the genetic cause of a proportion of cardiomyopathies associated with neuromuscular phenotype still remains unknown. Here, we present an individual with a combination of cardiomyopathy and limb-girdle type muscular dystrophy where whole exome sequencing identified myoferlin (MYOF)-a member of the Ferlin protein family and close homolog of DYSF-as the most likely candidate gene. The disease-causative role of the identified variant c.[2576delG; 2575G>C], p.G859QfsTer8 is supported by functional studies in vitro using the primary patient's skeletal muscle mesenchymal progenitor cells, including both RNA sequencing and morphological studies, as well as recapitulating the muscle phenotype in vivo in zebrafish. We provide the first evidence supporting a role of MYOF in human muscle disease.
| S-EPMC6607695 | biostudies-literature
Project description:A single nucleotide deletion in the stop codon of the nuclear import receptor transportin 3 (TNPO3), also involved in HIV infection, causes the ultrarare autosomal dominant disease limb-girdle muscular dystrophy D2 (LGMDD2) by adding 15 extra amino acids to the wild-type protein. Here, we generated the first patient-derived in vitro model of LGMDD2 as an immortalized myoblast cell line carrying the TNPO3 mutation. The cell model reproduced critical molecular alterations observed in patients, including TNPO3 overexpression, defects in terminal muscle markers, and autophagy overactivation. Correction of the LGMDD2 mutation by means of CRISPR-Cas9 edition produced a significant reversion of the pathological phenotypes in edited cells, including a complete absence of mutant TNPO3 protein using a polyclonal antibody specific against the abnormal 15 amino acid peptide. Transcriptomic analysis identified that 15% of the transcriptome was differentially expressed in model myotubes. CRISPR-Cas9 corrected cells showed that 44% of the alterations were rescued towards normal levels, including pathways involved in cell signalling and extracellular matrix structure. Globally, this work provides proof-of-concept of the potential of CRISPR-Cas9-mediated gene editing of TNPO3 as a therapeutic approach and describes critical reagents in LGMDD2 research.
2023-01-18 | GSE198551 | GEO
Project description:Activation of inflammatory pathways in transcriptome from patients affected by limb girdle muscular dystrophy D2 (LGMDD2)
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Project description:Comparative analysis of gene expression levels from hindlimb muscle tissue from 8 week old mouse models for muscular dystrophy. We have used mouse models with dystrophin-, sarcoglycan-, sarcospan-, or dysferlin-deficiency. Keywords = muscular dystrophy
2010-06-06 | E-GEOD-2112 | biostudies-arrayexpress
Project description:LGMDD2 is a rare form of muscular dystrophy characterized by a heterozygous deletion within the TNPO3 gen, firstly reported in a large Spanish family in 2001. TNPO3-wildtype is involved in the nuclear import of the essential splicing factors, a function altered in the mutated protein. Our group has shown that both TNPO3-wildtype and TNPO3-mutated proteins are translated in these patients. Besides its role in LGMDD2 disease, TNPO3 is also a HIV-1 co-factor but the mechanism underlying its antiviral action is still controversial. In an attempt to connect both LGMDD2 disease and HIV-1 infection, we demonstrated that PBMCs from LGMDD2 patients are refractory to in vitro HIV-1 infection due to a deficient viral integration subsequent to a deficient transport of the splicing factor CPSF6, due to TNPO3 mutation. The accumulation of HIV-1 capsid and retrotranscribed DNA in the cytosol may trigger anti-HIV inflammatory responses, therefore enhancing the blockade of HIV-1 replication. Further characterization of the crosstalk between HIV-1 infection and LGMDD2 disease may contribute to a better understanding of cellular alterations occurring in subjects living with LGMDD2. To this regard, here we show a high-throughput transcriptome profiling of PBMCs from LGMDD2 patients compared to their non-affected relatives. The differentially expressed genes were up-regulated and included G protein-coupled receptor binding chemokines, zinc ion binding proteins and metalloendopeptidases. The functional annotation showed an enrichment in immune response and inflammation pathways including IL-17, TNF, NOD-like receptor, TLR receptor, and NF-κβ signaling pathways, which are also known to be altered during HIV-1 infection. In summary, a holistic perspective of cellular changes occurring during LGMDD2 pathology is shown here providing new factors in this muscular dystrophy that may be considered in the design of new therapeutic strategies.
2022-05-10 | GSE193662 | GEO