Mutation Analysis of the Small Heat Shock Protein 27 Gene in Chinese Patients With Charcot-Marie-Tooth Disease

Tang, Beisha; Liu, Xiaomin; Zhao, Guohua; Luo, Wei; Xia, Kun; Pan, Qian; Cai, Fei; Hu, Zhengmao; Zhang, Cheng; Chen, Biao; Zhang, Fufeng; Shen, Lu; Zhang, Ruxu; Jiang, Hong

doi:10.1001/archneur.62.8.1201

Cited by 64 publications

(49 citation statements)

References 22 publications

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“…When the various CFP-tagged sHsp constructs were co-expressed with Cittagged R120G ␣BC [19] (Fig. 2C, panels a-e), we observed the recruitment of CFP-tagged WT ␣BC [18], Hsp20 [26], Hsp22 [27], and Hsp27 [28], into the aggregates (Fig. 2C, panels g-j), similar to what has been described previously (13).…”

Section: Intracellular Location and Phosphorylation Status Of Myopathsupporting

confidence: 85%

“…Which of the tissues actually is affected depends on the specific mutation, and currently it is not known what causes this clinical heterogeneity. In addition, two others sHsps, Hsp22 and Hsp27, have been associated with the human degenerative diseases Charcot-Marie-Tooth and distal hereditary motor neuron diseases (27)(28)(29)(30)(31)(32)(33). The first discovered sHsp mutation is the missense mutation R120G in ␣BC ( R120G ␣BC) (20), and to date this is the best studied mutation.…”

Section: ␣B-crystallin (␣Bc)mentioning

confidence: 99%

“…Finally, qFRET experiments were conducted with the intent to quantify possible differences in binding of the various MTT ␣BC species to Hsp27. Two series of experiments were performed using CFP-tagged Hsp27 [28], and Cit-tagged WT/MTT ␣BC species with the Cit moiety fused to the C terminus of the WT/MTT ␣BC species (vector group I, constructs 22-25) (supplemental Fig. 4C) or Cit-tagged WT/MTT ␣BC species with the Cit moiety fused to the N terminus of the WT/MTT ␣BC species (vector group II, constructs 18 -21) (supplemental Fig.…”

Section: Q151xmentioning

confidence: 99%

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Myopathy-associated αB-crystallin Mutants

Simon

Fontaine

Martin

et al. 2007

Journal of Biological Chemistry

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Three mutations (R120G, Q151X, and 464delCT) in the small heat shock protein ␣B-crystallin cause inherited myofibrillar myopathy. In an effort to elucidate the molecular basis for the associated myopathy, we have determined the following for these mutant ␣B-crystallin proteins: (i) the formation of aggregates in transfected cells; (ii) the partition into different subcellular fractions; (iii) the phosphorylation status; and (iv) the ability to interact with themselves, with wild-type ␣B-crystallin, and with other small heat shock proteins that are abundant in muscles. We found that all three ␣B-crystallin mutants have an increased tendency to form cytoplasmic aggregates in transfected cells and significantly increased levels of phosphorylation when compared with the wildtype protein. Although wild-type ␣B-crystallin partitioned essentially into the cytosol and membranes/organelles fractions, mutant ␣B-crystallin proteins partitioned additionally into the nuclear and cytoskeletal fractions. By using various protein interaction assays, including quantitative fluorescence resonance energy transfer measurements in live cells, we found abnormal interactions of the various ␣B-crystallin mutants with wild-type ␣B-crystallin, with themselves, and with the other small heat shock proteins Hsp20, Hsp22, and possibly with Hsp27. The collected data suggest that each ␣B-crystallin mutant has a unique pattern of abnormal interaction properties. These distinct properties of the ␣B-crystallin mutants identified are likely to contribute to a better understanding of the gradual manifestation and clinical heterogeneity of the associated myopathy in patients.

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Section: Intracellular Location and Phosphorylation Status Of Myopathsupporting

confidence: 85%

Section: ␣B-crystallin (␣Bc)mentioning

confidence: 99%

Section: Q151xmentioning

confidence: 99%

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Myopathy-associated αB-crystallin Mutants

Simon

Fontaine

Martin

et al. 2007

Journal of Biological Chemistry

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“…Furthermore, increased HSP27 levels in transgenic HSP27 mice rescue motor neurons and improve neuromuscular function following nerve injury (Sharp et al, 2006). All these studies suggest for a role of HSP27 in the pathogenesis of motor neuron degeneration.We and others identified mutations in HSP27 and its interacting partner HSP22 (small heat shock 22kDa protein 8: gene symbol HSPB8) in another motor neuron disease, distal hereditary motor neuropathy (distal HMN), supporting their pivotal role in motor neuron function Evgrafov et al, 2004;Tang et al, 2005;Kijima et al, 2005). The specific pathomechanism of these mutant small HSPs is unknown, however in vitro studies demonstrated the formation of intracellular aggregates, abnormal assembly of neurofilaments and a disturbance in axonal transport, pathological hallmarks probably triggering motor neuron death in ALS (Evgrafov et al, 2004;Ackerley et al, 2006).…”

mentioning

confidence: 70%

“…The neuroprotective effects of HSP27 may be related to its involvement in neurite extension and branching (Williams et al, 2006). Interestingly, mutations in HSPB1 were found in families with inherited peripheral neuropathies, distal HMN and Charcot-Marie-Tooth disease type 2, in particular (Evgrafov et al, 2004;Tang et al, 2005;Kijima et al, 2005). Although these studies strongly suggest a critical biological role for HSP27 in motor neurons, there is no information about the genetic contribution of HSPB1 to the etiology of the major motor neuron disease, sporadic ALS.…”

Section: Discussionmentioning

confidence: 99%

Genetic variant in theHSPB1 promoter region impairs the HSP27 stress response

et al. 2007

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The 27kDa heat shock protein 1 (HSP27) is a member of the ubiquitously expressed small heat shock protein family and has pleiotropic cytoprotective functions. Since HSP27 may act as a motor neuron survival factor, we analyzed the genetic contribution of the human HSPB1 gene (HSPB1) to the etiology of amyotrophic lateral sclerosis (ALS). In a cohort of sporadic ALS patients, we identified three rare genetic variations and one of which (c.-217T>C) targeted a conserved nucleotide of the Heat Shock Element (HSE) in the HSPB1 promoter. Since binding of Heat Shock Factor 1 (HSF1) to this HSE is essential for stressinduced transcription of HSPB1, we examined the effect of the c.-217C allele on transcriptional activity and HSF binding. The basal promoter activity of the HSPB1 c.-217C mutant allele decreased to 50% as compared to the wild-type promoter in neuronal and nonneuronal cells. Following heat shock, the HSE variant attenuated significantly the stressrelated increase in transcription. Electrophoretic mobility shift assays demonstrated a dramatically reduced HSF-binding to the c.-217C mutant allele as compared to the c.-217T wild-type allele. In conclusion, our study underscores the importance of the c.-217T nucleotide for HSF binding and heat inducibility of HSPB1. Therefore, our study suggests that the functional HSPB1 variant may represent a genetic modifier in the pathogenesis of motor neuron disease; however, it is necessary to confirm this HSPB1 variant in additional ALS patients. are likely multifactorial processes, including oxidative damage, aggregation, excitotoxicity, inflammation and neurofilament disorganization (Bruijn et al., 2004;Pasinelli and Brown, 2006). Some of these pathogenic processes are known to act as stress stimuli and induce a cellular heat shock response through stress-induced transcription of heat shock proteins (HSPs). Therefore an upregulation of HSPs is seen in several neuronal diseases including ALS (Vleminckx et al., 2002;Bidmon et al., 2004). These HSPs function as molecular chaperones in assisting the correct folding of denatured proteins and by inhibiting cell death pathways. The heat shock 27kDa protein 1 (HSP27: gene symbol HSPB1; MIM# 602195), is a member of the small heat shock protein family and is constitutively expressed in motor neurons (Plumier et al., 1997). Motor neurons upregulate the expression of HSP27 after peripheral nerve transection and this induction is crucial for their survival (Costigan et al., 1998;Benn et al., 2002;Kalmar et al., 2002). There is also increasing evidence for the neuroprotective capacities of HSP27 overexpression; e.g. simultaneous exogenous delivery of HSP27 and HSP70 (gene symbol HSPA1A) protects against copper-zinc superoxide dismutase 1 (SOD1)-mutant induced cell death in mammalian neuronal cells (Bruening et al., 1999;Wagstaff et al., 1999;Wyttenbach et al., 2002;Patel et al., 2005;Batulan et al., 2006), although overexpression of HSP27 alone is insufficient to obtain protection against the toxicity of mutant SOD1 . Furthermore, incr...

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Chaperoning Motor Neurons

Pleasure¹

2005

Arch Neurol

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Mutation Analysis of the Small Heat Shock Protein 27 Gene in Chinese Patients With Charcot-Marie-Tooth Disease

Cited by 64 publications

References 22 publications

Myopathy-associated αB-crystallin Mutants

Myopathy-associated αB-crystallin Mutants

Genetic variant in theHSPB1 promoter region impairs the HSP27 stress response

Chaperoning Motor Neurons

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