Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1

Nilsson, Johanna; Schöser, Benedikt; Laforêt, Pascal; Kalev, Ognian; Lindberg, Christopher; Romero, Norma B.; López, Marcela Dávila; Akman, Hasan O.; Wahbi, Karim; Iglseder, Stephan; Eggers, Christian; Engel, Andrew G.; DiMauro, Salvatore; Oldfors, Anders

doi:10.1002/ana.23963

Cited by 134 publications

(144 citation statements)

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“…Given that HOIP levels were lower in interferon-treated cpdm keratinocytes than in WT keratinocytes, augmented activation of antiapoptotic NF-B mediated by an increase in HOIL-1L/HOIP-containing LUBAC might not be able to completely override the augmented cell death caused by loss of SHARPIN. Some humans lacking HOIL-1L, however, exhibit autoinflammation and immunodeficiency in addition to amylopectinosis in early childhood (30), whereas in other cases, mutations in the HOIL-1L gene cause various degrees of myopathies without immunological symptoms beginning in childhood or the juvenile years (39,41). We have not observed any overt inflammatory diseases in HOIL-1L KO or HOIL-1L Ϫ/Ϫ SHARPIN ϩ/cpdm mice, at least by 12 weeks of age ( Fig.…”

Section: Discussionmentioning

confidence: 64%

Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

Shimizu

Fujita

Sasaki

et al. 2016

Molecular and Cellular Biology

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The linear ubiquitin chain assembly complex (LUBAC) participates in NF-κB activation and cell death protection. Loss of any of the three LUBAC subunits (catalytic HOIP, accessory HOIL-1L, or accessory SHARPIN subunit) leads to distinct phenotypes in mice and human. cpdm mice (chronic proliferative dermatitis in mice [cpdm]) that lack SHARPIN exhibit chronic inflammatory phenotypes, whereas HOIL-1L knockout mice exhibit no overt phenotypes, despite sharing highly homologous ubiquitin-like (UBL) and Npl4 zinc finger (NZF) domains. Here, we intercrossed mice lacking HOIL-1L and SHARPIN and found that reduction of HOIL-1L in cpdm mice exacerbated inflammatory phenotypes without affecting characteristic features of cpdm disease, whereas reduction of SHARPIN in HOIL-1L knockout mice provoked no overt phenotypes. Hence, loss of SHARPIN and reduction of LUBAC triggers cpdm phenotypes. We found that the NZF domain of SHARPIN, but not that of HOIL-1L, is critical for effective protection from programmed cell death by enhancing the recruitment of LUBAC to the activated TNFR complex. The binding activity to K63-linked ubiquitin chains that the NZF domain of SHARPIN, but not that of HOIL-1L, possesses appears to be involved in the recruitment. Thus, selective recognition of ubiquitin chains by NZFs in LUBAC underlies the regulation of LUBAC function.

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Section: Discussionmentioning

confidence: 64%

Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

Shimizu

Fujita

Sasaki

et al. 2016

Molecular and Cellular Biology

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“…A large deletion of 31 799 kb including the last three exons of TRIB3 and the first four exons of RBCK1 has been reported in three patients with immune dysfunction (Boisson et al, 2012). The same deletion has also been found in one patient with severe cardiomyopathy in addition to a possible but unconfirmed immune dysfunction (Nilsson et al, 2013). How this large deletion is related to the immune dysfunction remains to be established.…”

Section: Molecular Geneticsmentioning

confidence: 91%

“…Homozygous or compound heterozygous RBCK1 mutations are associated with early onset of disease, which includes polyglucosan accumulation in several tissues, skeletal myopathy, and rapidly progressing cardiomyopathy (Boisson et al, 2012;Nilsson et al, 2013;Wang et al, 2013). Two distinct phenotypes have been described.…”

Section: Clinical and Morphological Characteristicsmentioning

confidence: 99%

“…Two distinct phenotypes have been described. One group of patients presented with muscle weakness in the lower limbs, which was eventually followed by cardiac failure necessitating cardiac transplantation in several cases (Nilsson et al, 2013;Wang et al, 2013). Age at onset in this group varied from early childhood to adolescence.…”

Section: Clinical and Morphological Characteristicsmentioning

confidence: 99%

“…They contain ubiquitin and p62/sequestosome-1 (Fig. 15), and also cytoskeletal proteins such as desmin (Nilsson et al, 2013).…”

Section: Clinical and Morphological Characteristicsmentioning

confidence: 99%

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Polyglucosan storage myopathies

Hedberg‐Oldfors

Oldfors

2015

Molecular Aspects of Medicine

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Glycogen Storage Diseases

Cox

2017

Encyclopedia of Life Sciences

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Glycogen is a dense repository of energy which is present mostly in animal tissues; with its highly arborised structure, the glycogen dendrimer is a source of readily accessible glucose units at low osmotic cost. Access to, and accretion of glycogen is subject to fine metabolic and hormonal regulation; indeed, glycogen biosynthesis is driven by high‐energy phosphate‐bond energy, requiring also the participation of several unique protein complexes. Seminal research by Carl and Gerty Cori into the pathophysiology of glycogen metabolism opened up scientific universe of hormonal signalling, phosphorylation control and second messengers. That the glycogen storage disorder, Pompe disease, proved to be an inborn error affecting lysosome function demonstrated the crucial importance of lysosomal autophagy in cellular housekeeping. The polyglucosan body diseases, characterised by insoluble starch‐like deposits, reveal the critical role of macromolecular remodelling for the symmetrical compaction of branched glycogen structures to ensure that safe storage in the cytoplasm is combined with rapid metabolic access. Inherited defects in proteins which regulate glycogen metabolism, those which enact glycogenolysis and glycogen synthesis cause pathological glycogen accumulation – or prevent its formation. Defects in glycolysis also have consequential metabolic effects on glycogen storage. Latterly, at least eight human loci which harbour mutations associated with polyglucosan and Lafora body disease have been reported in these clinically diverse, but fatal, multisystem disorders. The principal defects identify pathways responsible for the unique control of glycogen metabolism in neurons; other conditions point to coregulation of glycogen metabolism and control of immune and inflammatory responses. Glycogen is an essential macromolecule, the adaptive advantages of which come at a cost. Disorders affecting the dynamic metabolism, regulation and maintenance of this vital energy source offer unique insights into a vast interactive network of molecular cell physiology. Key Concepts Glycogen is an essential intracellular macromolecule; its highly branched but compacted polymeric structure facilitates the rapid availability of glucose units for metabolic utilisation. With ≈55 000 linked glucose units, mature glycogen is a highly ordered sphere with a low intrinsic osmotic burden (molecular mass ≈ 10 7 Da). Glycogen is near ubiquitous in cells including neurons; but it is most abundant in muscle tissue, including cardiac muscle, and in the liver. Skeletal muscle provides the greatest net repository of glycogen for short‐lived bursts of ATP generation but the concentration in liver tissue is several‐fold greater. Liver glycogen is principally used to maintain interprandial glucose homeostasis. Appropriate molecular compaction of its symmetrical, highly branched structure maintains the solubility of glycogen in the cytoplasm – it also promotes access of metabolic enzymes, including complex protein assemblies which regulate the supply of glucose energy from its breakdown. To maintain optimal functional integrity, the branched structure of glycogen is constitutively remodelled by autophagy in the lysosomal compartment. With a short half‐life, glycogen undergoes dynamic interactions; its synthesis and degradation are subject to fine metabolic control. Inborn errors of biosynthesis and catabolism, including disorders of glycolysis, not only affect the abundance and availability of metabolic glucose released from intracellular glycogen but can also lead to altered glycogen storage and its macromolecular structure. Defects in proteins that regulate glycogen metabolism and transport, as well as those which catalyse its biosynthesis and breakdown, cause pathological – or defective – accumulation of glycogen in diverse tissues. Failure to synthesise glycogen and defective glycogenolysis lead to complex metabolic disturbances characterised by interprandial hypoglycaemia; accumulation of aberrant glycogen structures has additional pathological effects due to cellular toxicity. Glycogen storage disorders reveal much about the physiological biochemistry of glycogen and regulatory processes in the dynamic control of energy metabolism – including the special case of neuronal tissue.

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Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1

Cited by 134 publications

References 20 publications

Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

Polyglucosan storage myopathies

Glycogen Storage Diseases

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