A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot–Marie–Tooth disease type 2L

Nakhro, Khriezhanuo; Park, Jin Mo; Kim, Ye Jin; Yoon, Bo Ram; Yoo, Jeong Hyun; Koo, Heasoo; Choi, Byung Ok; Chung, Ki Wha

doi:10.1016/j.nmd.2013.05.009

Cited by 42 publications

(37 citation statements)

References 27 publications

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“…2,16 Clinically, the disease manifests as distal weakness affecting ankle dorsiflexion, eversion, and toe extension/flexion. In contrast to pure motor neuropathy, the muscle weakness progresses over the next 10-15 years to include proximal lower limb weakness with difficulties rising from the chair and a waddling gait in addition to the initial foot drop.…”

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confidence: 99%

“…In the previously reported patients with K141 mutations, a relatively unusual marked progression to significant proximal weakness was also reported clinically 15 and on muscle MRI. 16 We recommend that families with a dominant rimmed vacuolar myofibrillar myopathy and motor neuropathy should be screened for HSPB8 mutations. The K141E mutation alters the aggregation score compared to wildtype Transient cotransfection of an aggregation prone protein (GFP-120Q-HTT) and HSPB8 constructs results in a loss of ability to prevent aggregation in the mutant HSPB8 protein.…”

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Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

et al. 2016

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Objective: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes.Methods: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing.Results: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A . G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. Conclusion:We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects. Mutations in the small heat shock protein 22 gene (HSPB8, also called HSP22) located on chromosome 12q24.23 are associated with Charcot-Marie-Tooth type 2L (CMT2L) (OMIM 60673) 1 and distal hereditary motor neuronopathy type IIa (dHMN2A). 2 HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex, a vital part of the cellular protein quality control system in mechanically strained cells and tissues such as skeletal muscle, heart, and lung.3-5 HSPB8 has not been previously associated with a myopathy. The CASA complex comprises the molecular chaperones HSPA8 and HSPB8 and the cochaperones BAG3 and STUB1. 5 In muscle, CASA has a specific role in maintenance of the Z-disk and protein turnover.6,7 CASA mediates degradation of the actin cross-linking protein

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Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

et al. 2016

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“…Similar mutations in the ACD of Hsp22, (i.e. K141E [230], K141T [231] and K141N [230,232,233]), also give rise to CMT disease indicating a critical role for sHsps in motor and sensory neurons.…”

Section: Mutations In the -Crystallin Domainmentioning

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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“…2004). The list of variations associated with CMT and HMNs has greatly expanded and nowadays includes mutations which are propagated in both autosomal dominant and recessive manner (Houlden et al 2008;Ikeda et al 2009;Kim et al 2015;Nakhro et al 2013;Stancanelli et al 2015). The recent generation of mouse models has provided novel insights concerning the relation between HSP mutations and CMT.…”

Section: Shsps In Motor Neuropathiesmentioning

confidence: 99%

Small heat shock proteins in ageing and age-related diseases

Charmpilas

Kyriakakis

Tavernarakis

2017

Cell Stress and Chaperones

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Small heat shock proteins (sHSPs) are gatekeepers of cellular homeostasis across species, preserving proteome integrity under stressful conditions. Nonetheless, recent evidence suggests that sHSPs are more than molecular chaperones with merely auxiliary role. In contrast, sHSPs have emerged as central lifespan determinants, and their malfunction has been associated with the manifestation of neurological disorders, cardiovascular disease and cancer malignancies. In this review, we focus on the role of sHSPs in ageing and ageassociated diseases and highlight the most prominent paradigms, where impairment of sHSP function has been implicated in human pathology.

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A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot–Marie–Tooth disease type 2L

Cited by 42 publications

References 27 publications

Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

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

Small heat shock proteins in ageing and age-related diseases

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