DNAJB6 myopathy: A vacuolar myopathy with childhood onset

Suarez-Cedeno, Gerson; Winder, Thomas; Milone, Margherita

doi:10.1002/mus.24106

Cited by 22 publications

(25 citation statements)

References 14 publications

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“…Indeed, previous work in zebrafish similarly showed that the F89I mutation caused more severe muscle degeneration than the F93L mutation (2). This is also consistent with human LGMD1D; although the disease is typically late onset, patients with the F89I mutation have been reported to present with childhood onset weakness (47). Curiously, we found that the homologous F89I mutation in DNAJB1 was inviable in yeast, but its effect was not dominant.…”

Section: Discussionsupporting

confidence: 88%

Myopathy-causing Mutations in an HSP40 Chaperone Disrupt Processing of Specific Client Conformers

Stein

Bengoechea

Harms

et al. 2014

Journal of Biological Chemistry

100

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Background: Mutations in the G/F domain of the human HSP40 chaperone DNAJB6 cause a protein aggregate myopathy. Results: Homologous mutations in the yeast HSP40 Sis1 alter prion propagation in a prion strain-dependent manner. Conclusion: G/F domain mutations affect chaperone-mediated processing of particular client conformers. Significance: Impaired processing of certain substrate conformations may be one mechanism that contributes to chaperonopathy pathogenesis.

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Section: Discussionsupporting

confidence: 88%

Myopathy-causing Mutations in an HSP40 Chaperone Disrupt Processing of Specific Client Conformers

Stein

Bengoechea

Harms

et al. 2014

Journal of Biological Chemistry

100

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“…The previously reported mutations in DNAJB6 are known to cause adult-onset LGMD1D with mild to moderate progression and without respiratory muscle involvement [4][5][6][7][8]. The two novel mutations in DNAJB6 reported here, however, cause severe childhood-onset disease with reduced walking, contractures and progressive respiratory insufficiency with a loss of ambulation in early adulthood.…”

Section: Discussionmentioning

confidence: 51%

“…DNAJB6 belongs to a class of co-chaperones characterized by a J-domain in the N-terminus [5]. All four reported disease-causing coding mutations, p.F89I, p.F93I, p.F93L, and p.P96R, are located in the G/F-rich linker domain of DNAJB6 [4][5][6][7][8]. The previously reported mutations usually cause adult-onset, slowly progressive proximal muscle weakness.…”

Section: Introductionmentioning

confidence: 99%

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Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease

Palmio

Jonson

Evilä

et al. 2015

Neuromuscular Disorders

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DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T > A (p.F91I) and c.271T > C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation.

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“…Mutations in DnaJB6 (Mrj; mammalian relative of DnaJ), a 26/36 kDa J protein cause autosomal dominant limb-girdle muscular dystrophy type 1 D (Harms et al, 2012; Sarparanta et al, 2012; Sato et al, 2013; Suarez-Cedeno et al, 2014). Four mutations F96L, F96I, F89I and F93L results in adult or child onset (age 14–68 yrs) limb-girdle muscular dystrophy type 1D which is clinically characterized by elevated serum creatine kinase levels, progressive muscle weakness mainly in the legs.…”

Section: Dnajb6 (Mrj)mentioning

confidence: 99%

J protein mutations and resulting proteostasis collapse

Koutras

Braun

2014

Front. Cell. Neurosci.

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Despite a century of intensive investigation the effective treatment of protein aggregation diseases remains elusive. Ordinarily, molecular chaperones ensure that proteins maintain their functional conformation. The appearance of misfolded proteins that aggregate implies the collapse of the cellular chaperone quality control network. That said, the cellular chaperone network is extensive and functional information regarding the detailed action of specific chaperones is not yet available. J proteins (DnaJ/Hsp40) are a family of chaperone cofactors that harness Hsc70 (heat shock cognate protein of 70 kDa) for diverse conformational cellular tasks and, as such, represent novel clinically relevant targets for diseases resulting from the disruption of proteostasis. Here we review incisive reports identifying mutations in individual J protein chaperones and the proteostasis collapse that ensues.

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DNAJB6 myopathy: A vacuolar myopathy with childhood onset

Abstract: Childhood-onset of DNAJB6 myopathy is more frequent than previously believed; congophilic inclusions may be present in the muscle of these patients.

Cited by 22 publications

References 14 publications

Myopathy-causing Mutations in an HSP40 Chaperone Disrupt Processing of Specific Client Conformers

Myopathy-causing Mutations in an HSP40 Chaperone Disrupt Processing of Specific Client Conformers

Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease

J protein mutations and resulting proteostasis collapse

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