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Cells Feb 2020Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there... (Review)
Review
Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there are six ferlin genes encoding, in humans, dysferlin, otoferlin, myoferlin, Fer1L5 and 6 and the long noncoding RNA Fer1L4. Mutations in (dysferlin) can cause a range of muscle diseases with various clinical manifestations collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. A mutation in (myoferlin) was linked to a muscular dystrophy accompanied by cardiomyopathy. Mutations in (otoferlin) can be the cause of nonsyndromic deafness DFNB9. Dysregulated expression of any human ferlin may be associated with development of cancer. This review provides a detailed description of functions of the vertebrate ferlins with a focus on muscle ferlins and discusses the mechanisms leading to disease development.
Topics: Animals; Humans; Muscular Dystrophies, Limb-Girdle; Vertebrates
PubMed: 32106631
DOI: 10.3390/cells9030534 -
American Journal of Human Genetics Jun 2023Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the...
Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the mevalonate pathway, is the target of statins. We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing. The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation. Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry. Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization. Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability. In summary, we showed that individuals with bi-allelic amorphic (i.e., null and/or hypomorphic) variants in HMGCR display phenotypes that resemble non-genetic causes of myopathy involving this reductase. This study expands our knowledge regarding the mechanisms leading to muscular dystrophy through dysregulation of the mevalonate pathway, autoimmune myopathy, and statin-induced myopathy.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Muscular Dystrophies, Limb-Girdle; Muscular Diseases; Muscular Dystrophies; Oxidoreductases; Hydroxymethylglutaryl CoA Reductases
PubMed: 37167966
DOI: 10.1016/j.ajhg.2023.04.006 -
Journal of Clinical Medicine Jul 2023Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes. This review article presents 39 genes associated with LGMDs. Some forms are inherited... (Review)
Review
Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes. This review article presents 39 genes associated with LGMDs. Some forms are inherited in a dominant fashion, while for others this occurs recessively. The classification of LGMDs has evolved through time. Lately, to be considered an LGMD, the mutation has to cause a predominant proximal muscle weakness and must be found in two or more unrelated families. This article also presents therapies for LGMDs, examining both available treatments and those in development. For now, only symptomatic treatments are available for patients. The goal is now to solve the problem at the root of LGMDs instead of treating each symptom individually. In the last decade, multiple other potential treatments were developed and studied, such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene editing.
PubMed: 37510884
DOI: 10.3390/jcm12144769 -
Discoveries (Craiova, Romania) 2022Proximal myopathy presents as generalized muscle weakness commonly involving the muscles of upper and/or lower limbs. Toxins, long-term use of statins, corticosteroids,... (Review)
Review
Proximal myopathy presents as generalized muscle weakness commonly involving the muscles of upper and/or lower limbs. Toxins, long-term use of statins, corticosteroids, alcohol, SGLT2 inhibitors, COVID-19 vaccination, and antimalarials have been attributed to its development. In endocrine and metabolic disorders, adrenal dysfunction including both overproduction and insufficiency of the adrenal gland hormones has been reported to cause myopathy. Moreover, parathyroid and thyroid disorders along with pituitary gland disorders can also directly or indirectly contribute to this condition. In idiopathic inflammatory myopathies including polymyositis, dermatomyositis, inclusion body myositis (IBM), and Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome, and overlap syndromes, moderate to severe muscle weakness has been observed. IBM has been reported to be the most prevalent acquired myopathy above the age of 50. Hereditary or congenital myopathies include limb girdle muscular dystrophies, facioscapulohumeral muscular dystrophy, Duchenne and Becker muscular dystrophy, and proximal myotonic myopathy. In addition to these, glycogen storage diseases such as the McArdle disease can also cause fast exhaustion, myalgia, and cramping in working muscles. It is pertinent to mention here that a class of hereditary metabolic myopathies, referred to as "lipid deposition myopathy" causes lipids to accumulate in skeletal muscle fibers, leading to lesions and degeneration. Among viral causes, HIV, dengue virus, influenza virus, hepatitis B virus, hepatitis C virus, SARS-CoV2 are also associated with muscle weakness. Sarcoidosis, an inflammatory disease, can also manifest as muscle weakness and myalgia. Owing to this complicated pathophysiology of proximal myopathy, this review aims to summarize the existing literature on conditions associated with this phenomenon and other recent developments that have been made regarding events leading to development of generalized muscle weakness. To the authors' knowledge this is the first narrative review that discusses causes and conditions associated with proximal myopathy in thorough detail.
PubMed: 37483534
DOI: 10.15190/d.2022.19 -
Trends in Cell Biology Mar 2021Fukutin-related protein (FKRP) is a glycosyltransferase involved in the functional glycosylation of α-dystroglycan (DG), a key component in the link between the... (Review)
Review
Fukutin-related protein (FKRP) is a glycosyltransferase involved in the functional glycosylation of α-dystroglycan (DG), a key component in the link between the cytoskeleton and the extracellular matrix (ECM). Mutations in FKRP lead to dystroglycanopathies with broad severity, including limb-girdle and congenital muscular dystrophy. Studies over the past 5 years have elucidated the function of FKRP, which has expanded the number of therapeutic opportunities for patients carrying FKRP mutations. These include small molecules, gene delivery, and cell therapy. Here we summarize recent findings on the function of FKRP and describe available models for studying diseases and testing therapeutics. Lastly, we highlight preclinical studies that hold potential for the treatment of FKRP-associated dystroglycanopathies.
Topics: Dystroglycans; Glycosylation; Glycosyltransferases; Humans; Muscular Dystrophies; Pentosyltransferases
PubMed: 33272829
DOI: 10.1016/j.tcb.2020.11.003