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.

Keywords: Genetic dominance; Motor neuropathy; Mutation; Myopathy; Purifying selection; Small heat shock protein.

Figure 1. Positions of neuropathy- and myopathy-associated mutations in HspB1, HspB3, HspB5, HspB6, and HspB8 in the aligned ten human sHSPs

The domain designation is based on the previously published alignment [1]. Identical amino acid residues are highlighted in black if they occur in at least five sequences. Similar amino acid residues (E/D; A/G; H/F/W/Y; S/T; I/L/V; H/R/K) are highlighted in gray if they occur in at least five sequences, or if they occur in at least one sequence in addition to identical amino acid residues in five sequences. The position of the β7-strand secondary structure in HspB1, HspB5, and HspB8 is indicated below these sequences [24]. Positions affected by missense mutations are in red. The asterisk denotes amino acid residues that are conserved in all ten human sHSPs.

Figure 1. Positions of neuropathy- and myopathy-associated mutations in HspB1, HspB3, HspB5, HspB6, and HspB8 in the aligned ten human sHSPs

The domain designation is based on the previously published alignment [1]. Identical amino acid residues are highlighted in black if they occur in at least five sequences. Similar amino acid residues (E/D; A/G; H/F/W/Y; S/T; I/L/V; H/R/K) are highlighted in gray if they occur in at least five sequences, or if they occur in at least one sequence in addition to identical amino acid residues in five sequences. The position of the β7-strand secondary structure in HspB1, HspB5, and HspB8 is indicated below these sequences [24]. Positions affected by missense mutations are in red. The asterisk denotes amino acid residues that are conserved in all ten human sHSPs.