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European Journal of Human Genetics :... Jan 2023Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and...
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.
Topics: Infant; Mice; Animals; Humans; Child; Female; Cardiomyopathy, Dilated; Stroke Volume; Adaptor Proteins, Signal Transducing; LIM Domain Proteins; Ventricular Function, Left; Cardiomyopathies
PubMed: 36253531
DOI: 10.1038/s41431-022-01204-9 -
Journal of Clinical Neuromuscular... Sep 2022Myofibrillar myopathy is a clinically and genetically heterogeneous group of muscle disorders characterized by myofibrillar degeneration. Bcl-2-associated athanogene 3... (Review)
Review
Myofibrillar myopathy is a clinically and genetically heterogeneous group of muscle disorders characterized by myofibrillar degeneration. Bcl-2-associated athanogene 3 (BAG3)-related myopathy is the rarest form of myofibrillar myopathy. Patients with BAG3-related myopathy present with early-onset and progressive muscle weakness, rigid spine, respiratory insufficiency, and cardiomyopathy. Notably, the heterozygous mutation (Pro209Leu) in BAG3 is commonly associated with rapidly progressive cardiomyopathy in childhood. We describe a male patient with the BAG3 (Pro209Leu) mutation. The patient presented at age 7 years with muscle weakness predominantly in the proximal lower limbs. Histologic findings revealed a mixture of severe neurogenic and myogenic changes. His motor symptoms progressed rapidly in the next decade, becoming wheelchair-dependent by age 17 years; however, at the age of 19 years, cardiomyopathy was not evident. This study reports a case of BAG3-related myopathy without cardiac involvement and further confirmed the wide phenotypic spectrum of BAG3-related myopathy.
Topics: Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Cardiomyopathies; Humans; Male; Muscle Weakness; Mutation; Myopathies, Structural, Congenital; Phenotype
PubMed: 36005473
DOI: 10.1097/CND.0000000000000392 -
Clinical Neurology and Neurosurgery Oct 2022Skeletal muscle filaminopathy is caused by mutations in the gene encoding filamin C (FLNC). The phenotypes include both proximal and distal myopathy, of which proximal...
Skeletal muscle filaminopathy is caused by mutations in the gene encoding filamin C (FLNC). The phenotypes include both proximal and distal myopathy, of which proximal myopathy phenotype pathologically displays myofibrillar myopathy as mutated filamin C produces protein aggregates. FLNC-related myofibrillar myopathy usually starts in the fourth to fifth decade and often progresses to cause inability to walk, respiratory muscle weakness requiring nocturnal ventilation, and cardiac abnormalities, such as conduction blocks and diastolic dysfunction. We report a 65-year-old patient with myofibrillar myopathy caused by a novel heterozygous nonsense mutation in the dimerization domain of FLNC, in whom histopathological features were highlighted by histological and immunohistochemical studies. The reported patient showed slow progression of mild limb weakness since her childhood.
Topics: Codon, Nonsense; Dimerization; Female; Filamins; Humans; Muscle Weakness; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Pedigree; Protein Aggregates
PubMed: 35961230
DOI: 10.1016/j.clineuro.2022.107386 -
ELife Aug 2022Dystonin (), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. mutations cause...
Dystonin (), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. mutations cause different disorders, including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in -related diseases has been unclear. Because contains all of the -encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a -specific mutant mouse model harboring a nonsense mutation. mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in mutation-induced cardiomyopathy. RNA-sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.
Topics: Animals; Cardiomyopathies; Dystonin; Hereditary Sensory and Autonomic Neuropathies; Mice; Muscular Diseases; Mutation; Protein Aggregates; Protein Isoforms
PubMed: 35942699
DOI: 10.7554/eLife.78419 -
Journal of Neuropathology and... Aug 2022Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES...
Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes.
Topics: Cardiomyopathies; Desmin; Humans; Muscle, Skeletal; Mutation; Phenotype; Retrospective Studies
PubMed: 35898174
DOI: 10.1093/jnen/nlac063 -
Neuromuscular Disorders : NMD Aug 2022The diagnosis of adult-onset genetic muscle diseases is challenging because of the diversity of clinical phenotypes, findings on muscle biopsy that may be nonspecific,...
The diagnosis of adult-onset genetic muscle diseases is challenging because of the diversity of clinical phenotypes, findings on muscle biopsy that may be nonspecific, and the large number of genetic causes. Even with thorough investigation, the diagnostic yield for genetic testing in these populations is very low, and the distinction from acquired conditions such as sporadic inclusion body myositis [sIBM] can also prove difficult. In this study, we analysed whole transcriptome data generated from RNA isolated from muscle biopsy tissues, from a cohort of 16 participants with sIBM and other histologic diagnoses. Our objective was to identify candidate RNA biomarkers that could be an adjunctive tool in differentiating these conditions. Principal component analysis was able to delineate the groups based on their histologic diagnoses. Gene ontology and pathway analyses demonstrated dysregulation of immune pathways in sIBM. In mitochondrial myopathy we observed upregulation of FGF21, GDF15, ASNS and TRIB3, which are known candidate biomarkers for mitochondrial myopathy. Novel findings included the identification of transcripts of unknown function that were dysregulated in myofibrillar myopathy [JPX], dystrophic changes [MEG3], and mitochondrial myopathy [GAS5]. We suggest future investigations with larger cohorts of participants to confirm the findings of this study, with further directed experiments to determine the role of novel transcripts in disease pathogenesis.
Topics: Biomarkers; Biopsy; Gene Expression Profiling; Humans; Muscle, Skeletal; Myositis, Inclusion Body; RNA
PubMed: 35850946
DOI: 10.1016/j.nmd.2022.04.009 -
European Journal of Medical Genetics Aug 2022KY is located on chromosome 3 and encodes a transglutaminase-like protein in the skeletal muscles, namely Kyphoscoliosis Peptidase. KY is primarily involved in the... (Review)
Review
Genotypic and phenotypic spectrum of Myofibrillar Myopathy 7 as a result of Kyphoscoliosis Peptidase deficiency: The first description of a missense mutation in KY and literature review.
KY is located on chromosome 3 and encodes a transglutaminase-like protein in the skeletal muscles, namely Kyphoscoliosis Peptidase. KY is primarily involved in the formation and stabilization of neuromuscular intersections making it essential for the development of the musculoskeletal system. Mutations in KY cause Myofibrillar Myopathy-7 (MFM-7) and Hereditary Spastic Paraplegia (HSP). MFM-7 is an early onset muscle disorder with an autosomal recessive inheritance marked by progressive muscle weakness and joint contractures. Herein, we describe an Iranian family with MFM-7 caused by a homozygous novel variant in KY. We identified a homozygous variant (NM_178554.6:c.1247T > A, p. Ile416Asn) in KY in two patients born to consanguineous parents and the same heterozygous mutation in their parent by Whole-Exome Sequencing. The patients manifest muscle weakness, muscle atrophy, mobility restriction, and hyporeflexia. Lastly, we reviewed the phenotype and corresponding genotype of the previously reported cases with pathogenic variants in KY.
Topics: Homozygote; Humans; Iran; Muscle Weakness; Muscle, Skeletal; Mutation; Mutation, Missense; Myopathies, Structural, Congenital; Pedigree; Peptide Hydrolases; Phenotype; Spastic Paraplegia, Hereditary
PubMed: 35752288
DOI: 10.1016/j.ejmg.2022.104552 -
Neuromuscular Disorders : NMD May 2022Mutations in MEGF10 are associated with early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Recently, a mild variant phenotype of EMARDD has...
Mutations in MEGF10 are associated with early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Recently, a mild variant phenotype of EMARDD has been reported in patients with multiple minicores in the myofibers. However, some reported patients had no clear cores. We present a patient who had progressive weakness since his 30 s and then developed severe respiratory failure at the age of 66 years and found that he had a novel mutation, p.G739R, in MEGF10. He had no clear core in the biopsied muscle. We summarize the clinical and genetic characteristics of the current and reported patients with MEGF10 and statistically evaluate the genotype-phenotype correlation. Results show that patients with missense mutations in at least one allele had significantly later onset than those with biallelic truncation mutations.
Topics: Genotype; Humans; Male; Membrane Proteins; Muscle, Skeletal; Muscular Diseases; Mutation; Phenotype
PubMed: 35370044
DOI: 10.1016/j.nmd.2022.01.009 -
European Journal of Translational... Mar 2022Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength...
Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength and motility irreversibly impacts quality of life. In addition to directly affecting skeletal muscle, pathogenesis can also arise from dysfunctional crosstalk between nerves and muscles, and may include cardiac impairment. Muscular weakness is often progressive and paralleled by continuous decline in the ability of skeletal muscle to functionally adapt and regenerate. Normally, the skeletal muscle resident stem cells, named satellite cells, ensure tissue homeostasis by providing myoblasts for growth, maintenance, repair and regeneration. We recently defined 'Satellite Cell-opathies' as those inherited neuromuscular conditions presenting satellite cell dysfunction in muscular dystrophies and myopathies (doi:10.1016/j.yexcr.2021.112906). Here, we expand the portfolio of Satellite Cell-opathies by evaluating the potential impairment of satellite cell function across all 16 categories of neuromuscular disorders, including those with mainly neurogenic and cardiac involvement. We explore the expression dynamics of myopathogenes, genes whose mutation leads to skeletal muscle pathogenesis, using transcriptomic analysis. This revealed that 45% of myopathogenes are differentially expressed during early satellite cell activation (0 - 5 hours). Of these 271 myopathogenes, 83 respond to Pax7, a master regulator of satellite cells. Our analysis suggests possible perturbation of satellite cell function in many neuromuscular disorders across all categories, including those where skeletal muscle pathology is not predominant. This characterisation further aids understanding of pathomechanisms and informs on development of prognostic and diagnostic tools, and ultimately, new therapeutics.
PubMed: 35302338
DOI: 10.4081/ejtm.2022.10064