ABSTRACT Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue — encompassing the muscle

cells (myofibres) themselves and their extracellular matrix — or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular

disorder — mutations in dystrophin as an underlying cause of Duchenne muscular dystrophy — the field has made tremendous progress in understanding the genetic basis of these diseases, with

pathogenic variants in more than 500 genes now identified as underlying causes of neuromuscular disorders. The subset of neuromuscular disorders that affect skeletal muscle are referred to

resistance to stress and their primary activity in muscle contraction. In this Review, we discuss how defects in muscle proteins give rise to muscle dysfunction, and ultimately to disease,

with a focus on pathologies that are most common, best understood and that provide the most insight into muscle biology. Access through your institution Buy or subscribe This is a preview of

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IN FAST AND SLOW SKELETAL MYBP-C PARALOGS Article Open access 01 March 2023 DIGENIC INHERITANCE INVOLVING A MUSCLE-SPECIFIC PROTEIN KINASE AND THE GIANT TITIN PROTEIN CAUSES A SKELETAL

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their colleagues and laboratory members who provided important feedback on this Review including R. Crosbie, J. Chamberlain, E. McNally and A. Demonbreun. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada James J. Dowling * Division of Neurology and Program for Genetics and Genome

Biology, The Hospital for Sick Children Peter Gilgan Centre for Research and Learning (PGCRL), Toronto, Ontario, Canada James J. Dowling * Department of Neurology, Washington University

School of Medicine, St Louis, MO, USA Conrad C. Weihl * Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Melissa J. Spencer Authors * James J. Dowling

View author publications You can also search for this author inPubMed Google Scholar * Conrad C. Weihl View author publications You can also search for this author inPubMed Google Scholar *

Melissa J. Spencer View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS The authors contributed equally to all aspects of the article.

CORRESPONDING AUTHOR Correspondence to Melissa J. Spencer. ETHICS DECLARATIONS COMPETING INTERESTS M.J.S. is a co-founder of a startup called Myogene Bio. M.J.S. and C.C.W. serve on the

Research Advisory Board for the Muscular Dystrophy Association. J.M.D. is the Chief Medical Officer for Deep Genomics ADDITIONAL INFORMATION PEER REVIEW INFORMATION _Nature Reviews Molecular

Cell Biology_ thanks M. Sandri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. PUBLISHER’S NOTE Springer Nature remains neutral with regard to

jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION GLOSSARY * Reticular lamina One of the layers of the basement

membrane, composed of collagens I, III and VI. * Ambulation The ability to walk, unassisted. * Repeat expansions Duplication of untranslated regions of the genome. * Myotonic dystrophy

Multi-system disorders with the feature of an inability of muscles to relax after contraction. * Fascioscapulohumeral dystrophy Group of disorders due to failed regulation of the

developmental protein DUX4. * Syntrophins Adapter proteins linked to the cytoskeleton. * GRB2 Adapter protein often involved in coupling downstream signalling to cytoskeletal proteins. *

Becker muscular dystrophy (BMD). Disease that is allelic with Duchenne muscular dystrophy (DMD). BMD mutations are usually in-frame deletions and the phenotype is milder than in DMD. * Mdx

mouse model Murine model of Duchenne muscular dystrophy containing a premature termination codon in exon 23 of the _Dmd_ gene. * Walker–Warburg syndrome Congenital muscle disorders

manifesting as muscle weakness and eye and brain abnormalities. * Muscle–eye–brain disease Group of congenital muscle diseases that also impact the eye and brain, and are caused by abnormal

glycosylation of α-dystroglycan. * Bethlem myopathy Diseases due to mutations in collagen genes that result in defects in muscle and connective tissue. * Ullrich myopathy Congenital muscle

disorders due to mutations in genes encoding collagen VI. * Type 1 fibres Muscle fibres that are slow to fatigue and rely on oxidative metabolism. * Arthrogryposis Conditions involving

multiple joint contractures. * Type 2 fibres Muscle fibres that are quick to fatigue and rely on glycolytic metabolism. * Kelch domain A protein motif found in Kelch proteins, which are

adapters for cullin–E3 ubiquitin ligases. * Laing distal myopathy Muscle disease due to mutations in _MYH7_ that causes late onset of muscle weakness, initiating in distal muscles. * Myosin

storage myopathy A non-progressive muscle disorder involving excessive accumulation of myosin. * Centronuclear myopathy Group of muscle disorders that demonstrate the specific appearance of

small, centrally nucleated muscle fibres on a muscle biopsy sample. * Cores Structures on a muscle biopsy sample that lack NADH or SDH staining. * Emery–Dreifuss muscular dystrophy A group

of muscle diseases linked to mutations in either _FHL1_, _EMD_ or _LMNA_. * Central core disease Group of muscle disorders that demonstrate lack of histochemical staining as small holes or

‘cores’ on muscle biopsy samples. * Minicore myopathy Muscle disorders that show small holes or ‘minicores’ on muscle biopsy samples. * Congenital fibre type disproportion Muscle diseases

that show altered distribution of type 1 or type 2 muscle fibres. * Malignant hyperthermia A condition in which excessive calcium is released from the ryanodine receptor, leading to severe

spasms and increased heart rate. * Exertional rhabdomyolysis Muscle tissue breakdown that occurs after heavy muscle use. * SERCA A P-type calcium ATPase that pumps calcium back into the

sarcoplasmic reticulum following relaxation after muscle contraction. * Calcium calmodulin kinase II (CaMKII). Kinase that is activated by calcium–calmodulin, which in the muscle has been

shown to promote type 1 fibre gene expression for muscle adaptation to exercise. * Aldolase An enzyme, also known as fructose bisphosphate aldolase A, that catalyses the fourth step of

glycolysis. * Store-operated calcium entry A process that triggers calcium entry from the extracellular space in response to depletion of intracellular calcium stores. * Tubular aggregate

myopathy Muscle disease with appearance of tubular aggregates on biopsy samples. * Stormorken syndrome A rare condition associated with tubular aggregate myopathy in which many tissues are

affected. * Phosphatidylserine A phospholipid that is present in the sarcolemmal membrane on the cytoplasmic leaflet. * Synaptotagmin A C2-domain-containing (Ca2+ sensing) protein that is

typically involved in membrane trafficking. * EHD proteins A family of proteins containing the epidermal growth factor receptor pathway substrate 15 homology domain that are typically

involved in cellular trafficking. * Myoshi myopathy A muscle disorder due to mutations in the _DYSF_ gene. This disease is allelic with limb girdle muscular dystrophy type 2B, but manifests

with primarily distal muscle involvement. * Vici syndrome Developmental disorder that involves skeletal muscle, heart and other organ systems. * Danon disease Lysosomal storage disorder due

to mutations in _LAMP2_. * Pompe disease Lysosomal storage disorder affecting skeletal muscle and heart, related to aberrant glycogen accumulation. * X-linked myopathy with excessive

autophagy Childhood muscle disorder involving proximal muscle weakness due to disruption of an unidentified gene on the X chromosome. * Sarcotubular myopathy A muscle disorder demonstrating

membrane-enclosed vacuoles; allelic with limb girdle muscular dystrophy type 2H due to mutations in _TRIM32_. * Bardet–Biedl syndrome A group of rare disorders affecting multiple organs. *

Marinesco–Sjögren syndrome A multi-organ disease involving muscle weakness, ataxia and cataracts. * Selenocysteine protein family Proteins containing one or more selenocysteines, which are

amino acids that use selenium instead of sulfur in cysteine. * Mallory body myopathy Inclusions on a muscle biopsy sample that stain positively for desmin. * Exon skipping Therapeutic

strategy to restore the reading frame of a gene. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Dowling, J.J., Weihl, C.C. & Spencer, M.J. Molecular

and cellular basis of genetically inherited skeletal muscle disorders. _Nat Rev Mol Cell Biol_ 22, 713–732 (2021). https://doi.org/10.1038/s41580-021-00389-z Download citation * Accepted:

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