Novel <i>SPEG</i> mutations in congenital myopathies: Genotype–phenotype correlations

Qualls, Anita; Donkervoort, Sandra; Herkert, Johanna C.; D’Gama, Alissa M.; Bharucha‐Goebel, Diana; Collins, James J.; Chao, Katherine R.; Foley, A. Reghan; Schoots, Mirthe H.; Jongbloed, Jan D. H.; Bönnemann, Carsten G.; Agrawal, Pankaj B.

doi:10.1002/mus.26378

Cited by 16 publications

(25 citation statements)

References 17 publications

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“…Mutations in SPEG have recently been identified in patients with centronuclear myopathies (CNMs), a group of disorders characterized by severe muscle weakness with respiratory impairment, ophthalmoplegia, and scoliosis. Some CNM patients carrying homozygous or compound heterozygous SPEG mutations have been diagnosed with DCM, corroborating our findings implicating the SPEG E1680K mutation in DCM [ 31 , 32 ]. Unlike CNM patients who present with severe myopathies, the affected individuals in our index family presented with fulminant DCM without any clinical manifestation of myopathy.…”

Section: Discussionsupporting

confidence: 89%

A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

et al. 2020

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Dilated cardiomyopathy (DCM) is a common cause of heart failure and sudden cardiac death. It has been estimated that up to half of DCM cases are hereditary. Mutations in more than 50 genes, primarily autosomal dominant, have been reported. Although rare, recessive mutations are thought to contribute considerably to DCM, especially in young children. Here we identified a novel recessive mutation in the striated muscle enriched protein kinase (SPEG, p. E1680K) gene in a family with nonsyndromic, early onset DCM. To ascertain the pathogenicity of this mutation, we generated SPEG E1680K homozygous mutant human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) using CRISPR/Cas9-mediated genome editing. Functional studies in mutant iPSC-CMs showed aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization, recapitulating the hallmarks of DCM. By combining genetic analysis with human iPSCs, genome editing, and functional assays, we identified SPEG E1680K as a novel mutation associated with early onset DCM and provide evidence for its pathogenicity in vitro. Our study provides a conceptual paradigm for establishing genotype-phenotype associations in DCM with autosomal recessive inheritance.

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Section: Discussionsupporting

confidence: 89%

A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

et al. 2020

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“…The reported SPEG gene variants are all related to CNM. A total of 16 variant sites have been reported including the two sites we discovered in our study as shown in Table 1 [10,[14][15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic analysis of a case with centronuclear myopathy caused by SPEG gene mutation: a case report and literature review

Zhang

Huang

et al. 2021

BMC Pediatr

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Background Centronuclear myopathy (CNM), a subtype of congenital myopathy (CM), is a group of clinical and genetically heterogeneous muscle disorders. Since the discovery of the SPEG gene and disease-causing variants, only a few additional patients have been reported. Case presentation The child, a 13-year-old female, had delayed motor development since childhood, weakness of both lower extremities for 10 years, gait swinging, and a positive Gower sign. Her distal muscle strength of both lower extremities was grade IV. The electromyography showed myogenic damage and electromyographic changes. Her 11-year-old sister had a similar muscle weakness phenotype. Gene sequencing revealed that both sisters had SPEG compound heterozygous mutations, and the mutation sites were c.3715 + 4C > T and c.3588delC, which were derived from their parents. These variant sites have not been reported before. The muscle biopsy showed the nucleic (> 20% of fibers) were located in the center of the cell, the average diameter of type I myofibers was slightly smaller than that of type II myofibers, and the pathology of type I myofibers was dominant, which agreed with the pathological changes of centronuclear myopathy. Conclusions The clinical phenotypes of CNM patients caused by mutations at different sites of the SPEG gene are also different. In this case, there was no cardiomyopathy. This study expanded the number of CNM cases and the mutation spectrum of the SPEG gene to provide references for prenatal diagnosis and genetic counseling.

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“…Recessive mutations in SPEG (MIM 615950) have been linked to a clinically heterogeneous condition known as CNM with or without dilated cardiomyopathy (DCM) [ 8 , 42 , 43 , 44 ]. CNMs are a subtype of congenital myopathies (CM) clinically characterized by hypotonia and muscle dysfunction ranging in severity from mild delays in motor milestones to fatal weakness of respiratory organs [ 10 ].…”

Section: Speg Mutations In Myopathies and Cardiomyopathiesmentioning

confidence: 99%

Striated Preferentially Expressed Protein Kinase (SPEG) in Muscle Development, Function, and Disease

Luo

Rosen

et al. 2021

IJMS

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Mutations in striated preferentially expressed protein kinase (SPEG), a member of the myosin light chain kinase protein family, are associated with centronuclear myopathy (CNM), cardiomyopathy, or a combination of both. Burgeoning evidence suggests that SPEG plays critical roles in the development, maintenance, and function of skeletal and cardiac muscles. Here we review the genotype-phenotype relationships and the molecular mechanisms of SPEG-related diseases. This review will focus on the progress made toward characterizing SPEG and its interacting partners, and its multifaceted functions in muscle regeneration, triad development and maintenance, and excitation-contraction coupling. We will also discuss future directions that are yet to be investigated including understanding of its tissue-specific roles, finding additional interacting proteins and their relationships. Understanding the basic mechanisms by which SPEG regulates muscle development and function will provide critical insights into these essential processes and help identify therapeutic targets in SPEG-related disorders.

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Novel SPEG mutations in congenital myopathies: Genotype–phenotype correlations

Cited by 16 publications

References 17 publications

A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

Clinical and genetic analysis of a case with centronuclear myopathy caused by SPEG gene mutation: a case report and literature review

Striated Preferentially Expressed Protein Kinase (SPEG) in Muscle Development, Function, and Disease

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