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Brain : a Journal of Neurology Oct 2023Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc....
Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc. Pathogenic variants in filamin-encoding genes have been linked to neurological disorders (FLNA) and muscle diseases characterized by myofibrillar perturbations (FLNC), but human diseases associated with FILIP1 variants have not yet been described. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense). Functional studies indicated altered stability of the FILIP1 protein carrying the p.[Pro1133Leu] variant. Patients exhibit a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay, muscle weakness and pathology and dysmorphic features. Electron and immunofluorescence microscopy on the muscle biopsy derived from the patient harbouring the homozygous p.[Pro1133Leu] missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc. Proteomic studies on the fibroblasts derived from the same patient showed dysregulation of a variety of proteins including FLNc and alpha-B-crystallin, a finding (confirmed by immunofluorescence) which is in line with the manifestation of symptoms associated with the syndromic phenotype of FILIP1opathy. The combined findings of this study show that the loss of functional FILIP1 leads to a recessive disorder characterized by neurological and muscular manifestations as well as dysmorphic features accompanied by perturbed proteostasis and myopathology.
Topics: Humans; Filamins; Proteomics; Mutation; Muscular Diseases; Muscle Weakness; Carrier Proteins; Cytoskeletal Proteins
PubMed: 37163662
DOI: 10.1093/brain/awad152 -
Case Reports in Neurology 2020A 76-year-old man with a 5-year history of gait difficulties was suspected to have length-dependent sensorimotor polyneuropathy. Electrodiagnostic results pointed to a...
A 76-year-old man with a 5-year history of gait difficulties was suspected to have length-dependent sensorimotor polyneuropathy. Electrodiagnostic results pointed to a foot drop of neurogenic etiology, except for the prominence of myotonic discharges on needle EMG. Tests for acquired and genetic causes of polyneuropathy were unrevealing. The patient's first-degree cousin, with a much different clinical phenotype had been diagnosed with myofibrillar myopathy. Our patient was eventually found to carry the same myotilin c.179C>T p.Ser60Phe mutation. Muscle MRI was helpful in delineating clinically unsuspected involvement of paraspinal and pelvi-femoral muscles, as well as showing marked myopathic fatty infiltration of distal leg muscles. The association of neuropathy and myopathy is a recognized feature of myofibrillar myopathy. In some patients with unexplained foot drop, whole-body muscle MRI and a dedicated genetic mutation testing strategy may help reveal a diagnosis of genetic myopathy.
PubMed: 32647524
DOI: 10.1159/000506193 -
Equine Veterinary Journal Nov 2017To report a novel exertional myopathy, myofibrillar myopathy (MFM) in Warmblood (WB) horses.
BACKGROUND
To report a novel exertional myopathy, myofibrillar myopathy (MFM) in Warmblood (WB) horses.
OBJECTIVES
To 1) describe the distinctive clinical and myopathic features of MFM in Warmblood horses and 2) investigate the potential inheritance of MFM in a Warmblood family.
STUDY DESIGN
Retrospective selection of MFM cases and prospective evaluation of a Warmblood family.
METHODS
Retrospectively, muscle biopsies were selected from Warmblood horses diagnosed with MFM and clinical histories obtained (n = 10). Prospectively, muscle biopsies were obtained from controls (n = 8) and a three generation WB family (n = 11). Samples were assessed for histopathology [scored 0-3], fibre types, cytoskeletal and Z disc protein aggregates, electron microscopic alterations (EM) and muscle glycogen concentrations.
RESULTS
Myofibrillar myopathy-affected cases experienced exercise intolerance, reluctance to go forward, stiffness and poorly localised lameness. Abnormal aggregates of the cytoskeletal protein desmin were found in up to 120 type 2a and a few type 2x myofibres of MFM cases. Desmin positive fibres did not stain for developmental myosin, α actinin or dystrophin. Scores for internalised myonuclei (score MFM 0.83 ± 0.67, controls 0.22 ± 0.45), anguloid atrophy (MFM 0.95 ± 0.55, controls 0.31 ± 0.37) and total myopathic scores (MFM 5.85 ± 2.10, controls 1.41 ± 2.17) were significantly higher in MFM cases vs.
CONTROLS
Focal Z disc degeneration, myofibrillar disruption and accumulation of irregular granular material was evident in MFM cases. Muscle glycogen concentrations were similar between MFM cases and controls. In the Warmblood family, desmin positive aggregates were found in myofibres of the founding dam and in horses from two subsequent generations.
MAIN LIMITATIONS
Restricted sample size due to limited availability of well phenotyped cases.
CONCLUSIONS
A distinctive and potentially heritable form of MFM exists in Warmblood horses that present with exercise intolerance and abnormal hindlimb gait. Muscle tissue is characterised by ectopic accumulation of desmin and Z disc and myofibrillar degeneration.
Topics: Animals; Female; Genetic Predisposition to Disease; Horse Diseases; Horses; Male; Myopathies, Structural, Congenital
PubMed: 28543538
DOI: 10.1111/evj.12702 -
International Journal of Molecular... Jul 2023Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene...
Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene () result in a variety of diseases, including cardiomyopathies and myofibrillar myopathy, collectively called desminopathies. Here we describe the clinical, histological and radiological features of a Greek patient with a myofibrillar myopathy and cardiomyopathy linked to the c.734A>G,p.(Glu245Gly) heterozygous variant in the gene. Moreover, through ribonucleic acid sequencing analysis in skeletal muscle we show that this variant provokes a defect in exon 3 splicing and thus should be considered clearly pathogenic.
Topics: Humans; Desmin; Greece; Cardiomyopathies; Myopathies, Structural, Congenital; Muscle, Skeletal; Mutation; Muscular Diseases
PubMed: 37446359
DOI: 10.3390/ijms241311181 -
Clinical Medicine Insights. Cardiology 2016Arrhythmogenic right ventricular dysplasia (ARVD) is a rare, genetic disorder predominantly affecting the right ventricle. There is increasing evidence that in some... (Review)
Review
OBJECTIVES
Arrhythmogenic right ventricular dysplasia (ARVD) is a rare, genetic disorder predominantly affecting the right ventricle. There is increasing evidence that in some cases, ARVD is due to mutations in genes, which have also been implicated in primary myopathies. This review gives an overview about myopathy-associated ARVD and how these patients can be managed.
METHODS
A literature review was done using appropriate search terms.
RESULTS
The myopathy, which is most frequently associated with ARVD, is the myofibrillar myopathy due to desmin mutations. Only in a single patient, ARVD was described in myotonic dystrophy type 1. However, there are a number of genes causing either myopathy or ARVD. These genes include lamin A/C, ZASP/cypher, transmembrane protein-43, titin, and the ryanodine receptor-2 gene. Diagnosis and treatment are identical for myopathy-associated ARVD and nonmyopathy-associated ARVD.
CONCLUSIONS
Patients with primary myopathy due to mutations in the desmin, dystrophia myotonica protein kinase, lamin A/C, ZASP/cypher, transmembrane protein-43, titin, or the ryanodine receptor-2 gene should be screened for ARVD. Patients carrying a pathogenic variant in any of these genes should undergo annual cardiological investigations for cardiac function and arrhythmias.
PubMed: 27790050
DOI: 10.4137/CMC.S38446 -
Current Opinion in Neurology Oct 2013Myofibrillar myopathies (MFMs) are a heterogeneous group of skeletal and cardiac muscle diseases. In this review, we highlight recent discoveries of new genes and... (Review)
Review
PURPOSE OF REVIEW
Myofibrillar myopathies (MFMs) are a heterogeneous group of skeletal and cardiac muscle diseases. In this review, we highlight recent discoveries of new genes and disease mechanisms involved in this group of disorders.
RECENT FINDINGS
The advent of next-generation sequencing technology, laser microdissection and mass spectrometry-based proteomics has facilitated the discovery of new MFM causative genes and pathomechanisms. New mutations have also been discovered in 'older' genes, helping to find a classification niche for MFM-linked disorders showing variant phenotypes. Cell transfection experiments using primary cultured myoblasts and newer animal models provide insights into the pathogenesis of MFMs.
SUMMARY
An increasing number of genes are involved in the causation of variant subtypes of MFM. The application of modern technologies in combination with classical histopathological and ultrastructural studies is helping to establish the molecular diagnosis and reach a better understanding of the pathogenic mechanisms of each MFM subtype, thus putting an emphasis on the development of specific means for prevention and therapy of these incapacitating and frequently fatal diseases.
Topics: Animals; Genetic Predisposition to Disease; Humans; Muscle Proteins; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Phenotype
PubMed: 23995273
DOI: 10.1097/WCO.0b013e328364d6b1 -
Frontiers in Neurology 2018The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of...
OBJECTIVE
The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.
PATIENTS AND METHODS
Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.
RESULTS
Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in (c.1175C>T, p.Pro392Leu) and a heterozygous variant in (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness.
CONCLUSION
The findings indicate that all the affected individuals have a myopathy associated with both variants in and , respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the variant is a modifier of the mutation. We identify the combination of and variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.
PubMed: 29599744
DOI: 10.3389/fneur.2018.00147 -
Equine Veterinary Journal Mar 2021Myofibrillar myopathy (MFM) of unknown aetiology has recently been identified in Warmblood (WB) horses. In humans, 16 genes have been implicated in various MFM-like...
BACKGROUND
Myofibrillar myopathy (MFM) of unknown aetiology has recently been identified in Warmblood (WB) horses. In humans, 16 genes have been implicated in various MFM-like disorders.
OBJECTIVES
To identify variants in 16 MFM candidate genes and compare allele frequencies of all variants between MFM WB and non-MFM WB and coding variants with moderate or severe predicted effects in MFM WB with publicly available data of other breeds. To compare differential gene expression and muscle fibre contractile force between MFM and non-MFM WB.
STUDY DESIGN
Case-control.
ANIMALS
8 MFM WB, 8 non-MFM WB, 33 other WB, 32 Thoroughbreds, 80 Quarter Horses and 77 horses of other breeds in public databases.
METHODS
Variants were called within transcripts of 16 candidate genes using gluteal muscle mRNA sequences aligned to EquCab3.0 and allele frequencies compared by Fisher's exact test among MFM WB, non-MFM WB and public sequences across breeds. Candidate gene differential expression was determined between MFM and non-MFM WB by fitting a negative binomial generalised log-linear model per gene (false discovery rate <0.05). The maximal isometric force/cross-sectional area generated by isolated membrane-permeabilised muscle fibres was determined.
RESULTS
None of the 426 variants identified in 16 candidate genes were associated with MFM including 26 missense variants. Breed-specific differences existed in allele frequencies. Candidate gene differential expression and muscle fibre-specific force did not differ between MFM WB (143.1 ± 34.7 kPa) and non-MFM WB (140.2 ± 43.7 kPa) (P = .8).
MAIN LIMITATIONS
RNA-seq-only assays transcripts expressed in skeletal muscle. Other possible candidate genes were not evaluated.
CONCLUSIONS
Evidence for association of variants with a disease is essential because coding sequence variants are common in the equine genome. Variants identified in MFM candidate genes, including two coding variants offered as commercial MFM equine genetic tests, did not associate with the WB MFM phenotype.
Topics: Animals; Case-Control Studies; Female; Gene Expression; Horse Diseases; Horses; Male; Muscle, Skeletal; Myopathies, Structural, Congenital
PubMed: 32453872
DOI: 10.1111/evj.13286