Human Mutation in the Anti-apoptotic Heat Shock Protein 20 Abrogates Its Cardioprotective Effects

Nicolaou, Persoulla; Knöll, Ralph; Haghighi, Kobra; Fan, Guo-Chang; Dorn, Gerald W.; Hasenfuß, Gerd; Kranias, Evangelia G.

doi:10.1074/jbc.m802307200

Cited by 48 publications

(61 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, HspB6 is most closely related to HspB5, next to HspB4 [34]. The notion that the reported polymorphism in HspB6 is potentially associated with cardiomyopathy [14] suggests that HspB5 and HspB6 may form a 'myopathy group' among the sHSPs. The motor neuropathies associated with mutations in HspB1, HspB3, and HspB8 include distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease (CMT), whereas the myopathies associated with mutations in HspB5, and possibly with a polymorphism in HspB6, include various forms of cardiomyopathy (CM), notably desmin-related or myofibrillar myopathy (DRM, MM), dilated cardiomyopathy (DCM), and hypertonic infantile muscular dystrophy (HIMD), partially in combination with cataracts (C) in the lens of the eye (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the sHSP mutations with clearly associated diseases, sequence variants with unclear disease association have been found, representing mutations with low penetrance or rare polymorphisms. For example, a variant of HspB6 is suspected to be associated with the impaired ability of the heart to cope with pathological stress [14]. …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

Benndorf

Martin

Pond

et al. 2014

Mutation Research/Reviews in Mutation Research

View full text Add to dashboard Cite

Mutations in four of the ten human small heat shock proteins (sHSP) are associated with various forms of motor neuropathies and myopathies. In HspB1, HspB3, and HspB8 all known mutations cause motor neuropathies, whereas in HspB5 they cause myopathies. Several features are common to the majority of these mutations: (i) they are missense mutations, (ii) most associated disease phenotypes exhibit a dominant inheritance pattern and late disease onset, (iii) in the primary protein sequences, the sites of most mutations are located in the conserved α-crystallin domain and the variable C-terminal extensions, and (iv) most human mutation sites are highly conserved among the vertebrate orthologs and have been historically exposed to significant purifying selection. In contrast, a minor fraction of these mutations deviate from these rules: they are (i) frame shifting, nonsense, or elongation mutations, (ii) associated with recessive or early onset disease phenotypes, (iii) positioned in the N-terminal domain of the proteins, and (iv) less conserved among the vertebrates and were historically not subject to a strong selective pressure. In several vertebrate sHSPs (including primate sHSPs), homologous sites differ from the human sequence and occasionally even encode the same amino acid residues that cause the disease in humans. Apparently, a number of these mutations sites are not crucial for the protein function in single species or entire taxa, and single species even seem to have adopted mechanisms that compensate for potentially adverse effects of 'mutant-like' sHSPs. The disease-associated dominant sHSP missense mutations have a number of cellular consequences that are consistent with gain-of-function mechanisms of genetic dominance: dominant-negative effects, the formation of cytotoxic amyloid protein oligomers and precipitates, disruption of cytoskeletal networks, and increased downstream enzymatic activities. Future therapeutic concepts should aim for reducing these adverse effects of mutant sHSPs in patients. Indeed, initial experimental results are encouraging.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

Benndorf

Martin

Pond

et al. 2014

Mutation Research/Reviews in Mutation Research

View full text Add to dashboard Cite

show abstract

“…The levels of Hsp20 and its phosphorylation are increased on ischemic insults, and its overexpression protects the heart against ischemia-reperfusion injury (108). In addition, Hsp20 protects cardiomyocytes against apoptosis, and its phosphorylation at Ser16 enhances cardioprotection (96). PDE4 has been recently shown to directly bind to Hsp20 and to control cAMP levels around the Hsp20 complex.…”

Section: Localized Pdes Sustain Camp Compartmentalizationmentioning

confidence: 99%

Phosphodiesterases and subcellular compartmentalized cAMP signaling in the cardiovascular system

Stangherlin

Zaccolo

2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Phosphodiesterases are key enzymes in the cAMP signaling cascade. They convert cAMP in its inactive form 5'-AMP and critically regulate the intensity and the duration of cAMP-mediated signals. Multiple isoforms exist that possess different intracellular distributions, different affinities for cAMP, and different catalytic and regulatory properties. This complex repertoire of enzymes provides a multiplicity of ways to modulate cAMP levels, to integrate more signaling pathways, and to respond to the specific needs of the cell within distinct subcellular domains. In this review we summarize key findings on phosphodiesterase compartmentalization in the cardiovascular system.

show abstract

“…HSPs are upregulated in response to stress and exhibit a variety of cytoprotective effects through their function as molecular chaperones (40). A nonsynonymous polymorphism of HSP20 that lacks its characteristic cytoprotective effects has been described previously (41). However, none of the associated HSPB7 SNPs changed an amino acid in HSPB7.…”

Section: Applicability Of Pooled Resequencing With Next-generation Plmentioning

confidence: 99%

Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease

Matkovich¹,

Booven²,

Hindes³

et al. 2010

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Sporadic heart failure is thought to have a genetic component, but the contributing genetic events are poorly defined. Here, we used ultra-high-throughput resequencing of pooled DNAs to identify SNPs in 4 biologically relevant cardiac signaling genes, and then examined the association between allelic variants and incidence of sporadic heart failure in 2 large Caucasian populations. Resequencing of DNA pools, each containing DNA from approximately 100 individuals, was rapid, accurate, and highly sensitive for identifying common and rare SNPs; it also had striking advantages in time and cost efficiencies over individual resequencing using conventional Sanger methods. In 2,606 individuals examined, we identified a total of 129 separate SNPs in the 4 cardiac signaling genes, including 23 nonsynonymous SNPs that we believe to be novel. Comparison of allele frequencies between 625 Caucasian nonaffected controls and 1,117 Caucasian individuals with systolic heart failure revealed 12 SNPs in the cardiovascular heat shock protein gene HSPB7 with greater proportional representation in the systolic heart failure group; all 12 SNPs were confirmed in an independent replication study. These SNPs were found to be in tight linkage disequilibrium, likely reflecting a single genetic event, but none altered amino acid sequence. These results establish the power and applicability of pooled resequencing for comparative SNP association analysis of target subgenomes in large populations and identify an association between multiple HSPB7 polymorphisms and heart failure.

show abstract

Human Mutation in the Anti-apoptotic Heat Shock Protein 20 Abrogates Its Cardioprotective Effects

Cited by 48 publications

References 35 publications

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

Phosphodiesterases and subcellular compartmentalized cAMP signaling in the cardiovascular system

Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease

Contact Info

Product

Resources

About