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Neuropathy- and myopathy-associated mutations in human small heat shock proteins:
Characteristics and evolutionary history of the mutation sites
#MMPMID24607769
Benndorf R
; Martin JL
; Kosakovsky Pond SL
; Wertheim JO
Mutat Res Rev Mutat Res
2014[Jul]; 761
(?): 15-30
PMID24607769
show ga
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 ?-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.
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