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

Abstract

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.

Immense Cellular Implications Associated to Small Stress Proteins Expression: Impacts on Human Pathologies

“…Taken together these observations lead to the conclusion that small Hsps are benefi cial proteins that interfere with pathological processes leading to neurodegenerative, myopathic, cardiomyopathic, cataract and retinal diseases (Andley 2007 ;Firdaus et al 2006a ;Lee et al 2006 ;Outeiro et al 2006 ;Perrin et al 2007 ;Wilhelmus et al 2006a , b ;Wyttenbach et al 2002 ). This conclusion was further supported by mutations which inhibit the chaperone activity of HspB1, HspB3, HspB4, HspB5, HspB6 and HspB8 and provoke pathological diseases, such as amyotrophic lateral sclerosis (ALS), axonal Charcot-Marie-Tooth disease, inherited peripheral and motor neuropathies, myofi brillar myopathies, cardiomyopathies and cataracts (Ackerley et al 2005 ;Benndorf et al 2014 ;Bova et al 1999 ;Datskevich et al 2012 ;Dierick et al 2007 ;Elicker and Hutson 2007 ;Evgrafov et al 2004 ;Kijima et al 2005 ;Vicart et al 1998 ). However, depending on the clients that are recognized by these Hsps, the consequences of their mutations will vary, with HspB1, HspB3, and HspB8 causing motor neuropathies, while HspB5 induces particular myopathies called αB-crystallinopathies (Benndorf et al 2014 ).…”

“…Other important points concern the expression of these proteins in pathological conditions as well as the drastic effects (neuropathies, myopathies, cardiomyopathies, cataracts) induced by some of their mutations (i.e. mutations in HspB1, HspB3, HspB4, HspB5, HspB6 and HspB8) (Benndorf et al 2014 ;Kwok et al 2011 ;Mymrikov et al 2011 ;Vicart et al 1998 ). So, what is the function of these Hsps in specifi c tissues?…”

Interaction of small heat shock proteins with light component of neurofilaments (NFL)

“…Certain forms of distal hereditary motor neuropathy and Charcot-Marie-Tooth disease are also associated with mutations of small heat shock proteins (Benndorf et al 2014;Datskevich et al 2012). For instance, mutations G84R, L99M, R140G, K141Q, and P182S of HspB1 are associated with distal hereditary motor neuropathy of the second type (Benndorf et al 2014;Datskevich et al 2012).…”

“…For instance, mutations G84R, L99M, R140G, K141Q, and P182S of HspB1 are associated with distal hereditary motor neuropathy of the second type (Benndorf et al 2014;Datskevich et al 2012). Molecular mechanisms underlying probable participation of small heat shock proteins in distal hereditary motor neuropathy remain poorly characterized; however, it is well accepted that the small heat shock proteins can be involved in the interaction with different proteins of intermediate filaments.…”

Everything but the ACD, Functional Conservation of the Non-conserved Terminal Regions in sHSPs

“…Conversely the fact that across all kingdoms of life these regions are maintained in this state speaks to their importance and hints at conserved functional roles. This is probably best demonstrated by the identifi cation of congenital mutations within these two regions in a number of human homologues that are linked to the same disease state as those localized in the structured ACD (Benndorf et al 2014 ).…”