A novel variant of <i>RBCK1</i> gene causes mild polyglucosan myopathy

Alanzi, Talal; Harbi, Fahad Al; Alghamdi, Abdulaziz; Mohamed, Sarar

doi:10.17712/nsj.2022.1.20210681

Cited by 4 publications

(8 citation statements)

References 6 publications

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“…In addition to its ability to ubiquitylate serine and threonine residues in substrates, the LUBAC component HOIL-1 is also capable of ubiquitylating non-protein substrates ( Kelsall et al, 2022 ). Human patients deficient in HOIL-1 accumulate dense inclusions of insoluble starch-like polysaccharide in a number of organs including skeletal and cardiac muscle, resulting in cardiomyopathy and heart failure necessitating cardiac transplant ( Boisson et al, 2012 ; Nilsson et al, 2013 ; Wang et al, 2013 ; Fanin et al, 2015 ; Krenn et al, 2018 ; Phadke et al, 2020 ; Chen et al, 2021 ; AlAnzi et al, 2022 ; Krishnan et al, 2022 ). These precipitates, known as Polyglucosan Bodies, are also observed in the heart and brain of mice expressing catalytically inactive HOIL-1, establishing that the E3 ligase activity of the enzyme is required to prevent polyglucosan accumulation ( Kelsall et al, 2022 ).…”

Section: Non-protein Substratesmentioning

confidence: 99%

Non-lysine ubiquitylation: Doing things differently

Kelsall

2022

Front. Mol. Biosci.

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The post-translational modification of proteins with ubiquitin plays a central role in nearly all aspects of eukaryotic biology. Historically, studies have focused on the conjugation of ubiquitin to lysine residues in substrates, but it is now clear that ubiquitylation can also occur on cysteine, serine, and threonine residues, as well as on the N-terminal amino group of proteins. Paradigm-shifting reports of non-proteinaceous substrates have further extended the reach of ubiquitylation beyond the proteome to include intracellular lipids and sugars. Additionally, results from bacteria have revealed novel ways to ubiquitylate (and deubiquitylate) substrates without the need for any of the enzymatic components of the canonical ubiquitylation cascade. Focusing mainly upon recent findings, this review aims to outline the current understanding of non-lysine ubiquitylation and speculate upon the molecular mechanisms and physiological importance of this non-canonical modification.

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Section: Non-protein Substratesmentioning

confidence: 99%

Non-lysine ubiquitylation: Doing things differently

Kelsall

2022

Front. Mol. Biosci.

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“…5 A correlation exists between genotype and phenotype, whereby mutations located in the N-terminal region of RBCK1 may increase the likelihood of immunodeficiency in affected patients, while mutations in the middle or C-terminal region may lead to the development of myopathic symptoms. 26 Mutations in RBCK1 cause PGBM1, a type of glycogen storage disease. Based on available evidence, the hallmark of RBCK1 mutations is skeletal muscle involvement, present in all reported patients.…”

Section: Discussionmentioning

confidence: 99%

“…Proximal lower limb muscles are predominantly involved, with the clinical manifestations varying among patients, including cardiomyopathy, systemic auto-inflammation, immunodeficiency, hepatomegaly, and cognitive impairment. [1][2][3]6,8,[26][27][28] In the current study, we presented a new missense variant of RBCK1, c.598_599insT: p.His200LeufsTer14, in a 7-year-old girl manifesting with DCM leading to heart transplantation and proximal skeletal muscle weakness. Mutations that impact transcript size, such as deletions, insertions, and nonsense mutations, are more prevalent in this particular gene and exhibit a more pronounced phenotype than missense mutations.…”

Section: Discussionmentioning

confidence: 99%

“…The primary manifestation of this condition is the development of cardiomyopathy and neuromuscular symptoms. 26 Krenn et al suggested that the exact location of the mutations within the gene correlated with the clinical presentation of the disease and concluded that while N-terminal mutations mostly presented with immunological dysfunction, middle and C-terminal part mutations led to cardiomyopathy. 3 The updated mapping of clinical manifestations on protein domains in the present study was also consistent with that in prior studies, and N-terminal mutations presented immunodeficiency and auto-inflammation more often.…”

Section: Discussionmentioning

confidence: 99%

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A novel likely pathogenic homozygous RBCK1 variant in dilated cardiomyopathy with muscle weakness

MozafaryBazargany,

Esmaeili,

Hesami

et al. 2024

ESC Heart Failure

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AimsPolyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease where polyglucosan accumulation leads to cardiomyopathy and skeletal muscle myopathy. Variants of RBCK1 is related with PGBM1. We present a newly discovered pathogenic RBCK1 variant resulting in dilated cardiomyopathy (DCM) and a comprehensive literature review.Methods and resultsWhole‐exome sequencing (WES) was utilized to detect genetic variations in a 7‐year‐old girl considered the proband. Sanger sequencing was performed to validate the variant in the patient and all the available family members, whether affected or unaffected. The variant's pathogenicity was assessed by conducting a cosegregation analysis within the family with in silico predictive software. WES showed that the proband's RBCK1 gene contained a missense likely pathogenic homozygous nucleotide variant, c.598_599insT: p.His200LeufsTer14 (NM_001323956.1), in exon 8. The computational analysis supported the variant's pathogenicity. The variant was identified in a heterozygous form among all the healthy members of the family. Variants with changes in N‐terminal part of the protein were more likely to manifest immunodeficiency and auto‐inflammation than those with C‐terminal protein modifications according to prior variations of RBCK1 reported in the literature.ConclusionsOur study offers novel findings indicating an RBCK1 variant in individuals of Iranian ancestry presenting with DCM leading to heart transplantation and myopathy without immunodeficiency or auto‐inflammation.

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“…(3) Recently, another E3 ubiquitin ligase, RBCK1, was shown to ubiquitinate glycogen and even more so long-chained glucans in vitro ( Kelsall et al, 2022 ). Loss of RBCK1 function results in polyglucosan accumulation and a distinct disease, characterized by fatal skeletal and cardiac myopathy ( AlAnzi et al, 2022 ; Boisson et al, 2012 ; Chen et al, 2021 ; Nilsson et al, 2013 ; Phadke et al, 2020 ; Wang et al, 2013 ). Hypotheses along these lines suggest that the laforin–malin complex functions in actively clearing polyglucosans.…”

Section: Discussionmentioning

confidence: 99%

Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy

Mitra

Chen

Wang

et al. 2023

Disease Models &Amp; Mechanisms

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Glycogen is the largest cytosolic macromolecule and kept in solution through a regular system of short branches allowing hydration. This structure was thought to solely require balanced glycogen synthase and branching enzyme activities. Deposition of overlong-branched glycogen in the fatal epilepsy Lafora disease (LD) indicated involvement of the LD gene products laforin and the E3 ubiquitin ligase malin in regulating glycogen structure. Laforin binds glycogen, and LD-causing mutations disrupt this binding, laforin-malin interactions, or malin's ligase activity, all indicating a critical role for malin. Neither malin's endogenous function nor location could to date be studied due to lack of suitable antibodies. We generated a mouse in which the native malin gene is tagged with the FLAG sequence. We show that the tagged gene expresses physiologically, malin localizes to glycogen, laforin and malin indeed interact, at glycogen, and that malin's presence at glycogen depends on laforin. These results, and mice, open the way to understanding unknown mechanisms of glycogen synthesis critical to LD, and potentially other much more common diseases due to incompletely understood defects in glycogen metabolism.

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A novel variant of RBCK1 gene causes mild polyglucosan myopathy

Cited by 4 publications

References 6 publications

Non-lysine ubiquitylation: Doing things differently

Non-lysine ubiquitylation: Doing things differently

A novel likely pathogenic homozygous RBCK1 variant in dilated cardiomyopathy with muscle weakness

Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy

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