Exploring Obscurin and SPEG Kinase Biology

Fleming, Jennifer R.; Rani, Alankrita; Kraft, Jamie; Zenker, Sanja; Börgeson, Emma; Lange, Stephan

doi:10.3390/jcm10050984

Cited by 15 publications

(15 citation statements)

References 73 publications

(151 reference statements)

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“…SPEG encodes a serine/threonine-specific protein kinase that belongs to the Obscurin/MLCK (also known as MYLK) family ( Fleming et al, 2021 ). SPEG contains two serine/threonine kinase domains, two Fibronectin-Type III (Fn) domains and nine Immunoglobulin (Ig) domains ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy

Espinosa

Geissah

Groom

et al. 2022

Disease Models &Amp; Mechanisms

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Centronuclear myopathy (CNM) is a congenital neuromuscular disorder caused by pathogenic variation in genes associated with membrane trafficking and excitation-contraction coupling (ECC). Bi-allelic autosomal recessive mutations in striated muscle enriched protein kinase (SPEG) account for a subset of CNM patients. Previous research has been limited by the perinatal lethality of constitutive Speg knockout mice. Thus, the precise biological role of SPEG in developing skeletal muscle remains unknown. To address this issue, we generated zebrafish spega, spegb, and spega;spegb (speg-DKO) mutant lines. We demonstrate that speg-DKO zebrafish faithfully recapitulate multiple phenotypes associated with CNM, including disruption of the ECC machinery, dysregulation of calcium homeostasis during ECC, and impairment of muscle performance. Taking advantage of zebrafish models of multiple CNM genetic subtypes, we compared novel and known disease markers in speg-DKO with mtm1-KO and DNM2-S619L transgenic zebrafish. We observed desmin accumulation common to all CNM subtypes, and DNM2 upregulation in muscle of both speg-DKO and mtm1-KO zebrafish. In all, we establish a new model of SPEG-related CNM, and identify abnormalities in this model suitable for defining disease pathomechanisms and evaluating potential therapies.

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Section: Introductionmentioning

confidence: 99%

Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy

Espinosa

Geissah

Groom

et al. 2022

Disease Models &Amp; Mechanisms

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“…Obscurin is thus proposed to play a key role linking the contractile apparatus to the SR. Obscn null 27 Obscurin's precise role in skeletal muscle development, function and disease has remained obscure. 50 It had been shown in C. elegans, D. Melanogaster and D. Rerio that obscurin and its homologue unc-89 might play an important role in sarcomerogenesis and the lateral alignment of sarcomeres. [51][52][53] However, studies by Lange and colleagues of Obscn null mice failed to identify any defects in sarcomere structure and alignment.…”

Section: Discussionmentioning

confidence: 99%

Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis

Cabrera‐Serrano

Caccavelli

Savarese

et al. 2021

Brain

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Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, most cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified ten bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) predisposing individuals to recurrent rhabdomyolysis. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in SR function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in SR Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the SR and/or a decrease in Ca2+ SR storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.

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“…The identity of the kinase in SPEG responsible for phosphorylating RyR2 remains unknown [ 14 ]. It is speculated that RyR2 is modified by the SK1 of SPEG since RyR2 can be modified by the first kinase domain of obscurin which is very similar to the SK-1 of SPEG [ 104 ].…”

Section: Speg and Its Interacting Partnersmentioning

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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Exploring Obscurin and SPEG Kinase Biology

Cited by 15 publications

References 73 publications

Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy

Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy

Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis

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

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