Infantile muscular dystrophy in Canadian aboriginals is an αB‐crystallinopathy

Bigio, Marc R. Del; Chudley, Albert E.; Sarnat, Harvey B.; Campbell, Craig; Goobie, Sharan; Chodirker, Bernard N.; Selcen, Duygu

doi:10.1002/ana.22331

Cited by 64 publications

(46 citation statements)

References 23 publications

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“…Similarly, several other naturally-occurring mutations in the C-terminal region of Hsp27; P182L [229], P182S [237], R140G [238] and K141Q [239] cause distal HMN. Other rarer forms of fibrillar neuropathy have been identified, with deletions in the gene encoding Bc (CRYAB) resulting in the absence of the protein from affected muscle fibres [240]. A naturally-occurring deletion of a single nucleotide base in the CRYAB gene has been described and leads to a frameshift mutation in the C-terminal region of the resulting Bc protein [216].…”

Section: Mutations In the C-terminal Regionmentioning

confidence: 99%

Small heat-shock proteins: important players in regulating cellular proteostasis

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

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Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of posttranslational modifications in sHsp chaperone function, particularly in the context of disease. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract (word count = 159)Small heat-shock proteins (sHsps) are a diverse family of intracellular molecular chaperone proteins that play a critical role in preventing protein unfolding, misfolding and aggregation, particularly under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) and thereby avoid the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. There has been much research into the structure and mechanism of chaperone action of sHsps over approximately the past 30 years, and significant progress has been made of late, however, there are still many unanswered questions relating to these aspects of sHsps. In this review, we outline some of the recent advances in understanding the structure and function of mammalian sHsps, particularly in the context of their many and varied roles in disease.

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Section: Mutations In the C-terminal Regionmentioning

confidence: 99%

Small heat-shock proteins: important players in regulating cellular proteostasis

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

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“…For example, myotilinopathy was reported as limb girdle muscular dystrophy 1A by the clinical criteria, 36,37 and the ␣B-crystallinopathy of Canadian aboriginals was reported under the rubric of a fatal infantile muscular dystrophy. 38,39 Finally, the clinical and pathologic features of the FHL1 muscular dystrophies can be typical of MFMs, but MFM pathology has not been described or may have been overlooked in some cases of FHL1-related muscular dystrophies. The presence of reducing bodies points to a mutation in the LIM2 domain of FHL1.…”

Section: Org)mentioning

confidence: 99%

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Selcen

Bromberg

Chin³

et al. 2011

Neurology

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Objective: Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM. Methods:Mutations in FHL1 were identified by direct sequencing. Polymorphisms were excluded by using allele-specific PCR in 200 control subjects. Structural changes in muscle were analyzed by histochemistry, immunocytochemistry, and electron microscopy. Results:We detected 2 novel and 1 previously identified missense mutation in 5 patients. Patients 1-4 presented before age 30, display menadione-nitro blue tetrazolium-positive reducing bodies, and harbor mutations in the FHL1 LIM2 domain. Patient 5 presented at age 75 and has no reducing bodies, and his mutation is not in a LIM domain. The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures, and 1 patient also has peripheral neuropathy. High-resolution electron microscopy reveals the reducing bodies composed of 13-nm tubulofilaments initially emanating from Z-disks. At a more advanced stage, abundant reducing bodies appear in the cytoplasm and nuclei with concomitant myofibrillar disintegration, accumulation of cytoplasmic degradation products, and aggregation of endoplasmic reticulum and sarcotubular profiles. The four-and-a-half LIM domain protein 1 (FHL1), encoded by FHL1, is located on Xq26.3. It is highly expressed in skeletal and cardiac muscle and less abundantly in brain, placenta, lung, liver, kidney, pancreas, and testis.1-3 Mutations in FHL1 have been associated with diverse chronic myopathies. 4 These include late-onset X-linked scapulo-axio-peroneal myopathy with bent spine syndrome, 5 reducing body myopathy, 6,7 X-linked dominant scapuloperoneal muscular dystrophy, 8 rigid spine syndrome, 9 and contractures and cardiomyopathy mimicking Emery-Dreifuss muscular dystrophy. 10,11 Most FHL1 mutations appear in the second or fourth LIM domains with a single mutation in the third LIM domain.Myofibrillar myopathies (MFMs) arise from primary degeneration of the muscle fibers and represent a morphologically distinct but genetically heterogeneous subset of muscular dystrophies. The unifying histologic findings are early disintegration of the Z-disk followed by myofibrillar disintegration, aggregation of degraded filaments into pleomorphic granular or hyaline inclusions, and ectopic expression of multiple Z-disk-related and other proteins in the affected muscle fibers.12-14 Although some pathologic features of the FHL1 muscular dystrophies and the MFMs overlap, reducing bodies have been detected only in FHL1 dystrophies. 7,15 We here report 2 novel

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“…This may be similar to muscles of patients with the R120G mutation who have loss of myosin in their muscle cells (Vicart et al 1998 ;Fardeau et al 1978 ). Potentially, oxidative, slow-twitch fi bers, which have the highest levels of αB-crystallin and are enriched in large truncal muscles, are preferentially degraded in the DKO mice (Brady et al 2001 ) and in patients with recessive CRYAB mutations (Forrest et al 2011 ;Del Bigio et al 2011 ). Neppl and colleagues showed that 1 year old DKO mice have a signifi cantly reduced number of satellite cells in their skeletal muscle and a reduced ability to regenerate muscle following cardiotoxin-induced injury, shown by decreased cross-sectional myofi ber area and increased fi brosis 2 weeks post-injury, indicating a potential role for αB-crystallin in skeletal muscle regeneration (Neppl et al 2014 ).…”

Section: Recessive Mutationsmentioning

confidence: 98%

Multifunctional Roles of αB-Crystallin in Skeletal and Cardiac Muscle Homeostasis and Disease

Mitzelfelt

Benjamin

2015

Heat Shock Proteins

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αB-Crystallin, or HspB5, is a small molecular-weight heat shock protein expressed highly in cardiac and skeletal muscle with multifaceted cellular roles including, chaperone function towards essential myofi brillar components. Insights into protective roles played by αB-crystallin, as well as mutations in the gene encoding αB-crystallin, CRYAB , which resulted in human pathologies, have highlighted the critical functions of αB-crystallin in both skeletal and cardiac muscle, inter alia . Various human mutations in CRYAB appear to have tissue-specifi c effects, with loss of αB-crystallin only impacting skeletal muscle under basal conditions. This review aims to highlight the roles of αB-crystallin in skeletal and cardiac muscle homeostasis as well as under conditions of stress and disease, drawing insights from human pathologies resulting from CRYAB mutations, and to discuss the potential of using induced pluripotent stem cells to model αB-crystallin-opathies in vitro.

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Infantile muscular dystrophy in Canadian aboriginals is an αB‐crystallinopathy

Cited by 64 publications

References 23 publications

Small heat-shock proteins: important players in regulating cellular proteostasis

Small heat-shock proteins: important players in regulating cellular proteostasis

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Multifunctional Roles of αB-Crystallin in Skeletal and Cardiac Muscle Homeostasis and Disease

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