Abstract
Two chaperonopathies have been linked to mutations in the human hsp60 (hHsp60; HSPD1) gene, but other existing variants might cause diseases, even if there is no comprehensive information about this possibility. To fill this vacuum, which might be at the basis of misdiagnoses or simply ignorance of chaperonopathies in patients who would benefit by proper identification of their ailments, we searched the sequenced human genomes available in public databases to determine the range of missense mutations in the single hsp60 gene. A total of 224 missense mutations were identified, including those already characterized. Detailed examination of these mutations was carried out to assess their possible impact on protein structure-function, considering: (a) the properties of individual amino acids; (b) the known functions of the amino acids in the human Hsp60 and/or in the highly similar bacterial ortholog GroEL; (c) the location of the mutant amino acids in the monomers and oligomers; and (d) structure-function relationships inferred from crystal structures. And we also applied a bioinformatics tool for predicting the impact of mutations on proteins. A portion of these genetic variants could have a deleterious impact on protein structure-function, but have not yet been associated with any pathology. Are these variants causing disease with mild clinical manifestations and are, therefore, being overlooked? Or are they causing overt disease, which is misdiagnosed? Our data indicate that more chaperonopathies might occur than is currently acknowledged and that awareness of chaperonopathies among medical personnel will increase their detection and improve patient management.
Highlights
Hsp60, termed human hsp60 (hHsp60) or HSPD1 in humans, is an essential chaperone typically residing in the mitochondria and chloroplasts of eukaryotes and considered to have been derived from the ancestor of the bacterial counterpart currently known as GroEL
They are: (1) a dominantly inherited form of spastic paraplegia – Spastic paraplegia 13 (SPG13) (OMIM #605280), which is caused by the p.V98I and the p.Q461E missense mutations (Fontaine et al, 2000; Hansen et al, 2002, 2007); and (2) a recessively inherited hypomyelinating leukodystrophy – HDL4 (OMIM #612233), caused by the p.D29G missense mutation (Magen et al, 2008; Kusk et al, 2016)
A comprehensive search of known human HSPD1 missense mutations was carried out, and the data were tabulated, using information from the literature and three databases: the Genome Aggregation Database, which includes exome and genome sequencing data from a variety of large-scale sequencing projects; the NHLBI GO Exome Sequencing Project [Exome Variant Server, NHLBI Exome Sequencing Project (ESP), Seattle, WA2], whose objectives are to reveal novel genes implicated in heart, lung, and blood pathological conditions, using next-generation sequencing of human exomes; and the ClinVar database3, curated by the National Center for Biotechnology Information (NCBI)
Summary
Hsp, termed hHsp or HSPD1 in humans, is an essential chaperone typically residing in the mitochondria (mHsp60) and chloroplasts of eukaryotes and considered to have been derived from the ancestor of the bacterial counterpart currently known as GroEL. The double-ring tetradecameric complex is known for its intrinsic instability, since the purification attempts have shown that the mHsp is unstable and tends to dissociate into monomers at low temperatures and low protein concentrations (Viitanen et al, 1998; Vilasi et al, 2018) In solution it exists in dynamic equilibrium between monomers, heptameric single rings and double-ring tetradecamers, and only the presence of both ATP and Hsp favors the formation of the functional football complex (Levy-Rimler et al, 2001). The described instability of hHsp in vitro has hindered further investigations, and for this reason, the molecular mechanisms leading to disease-development associated with HSPD1 mutations are not yet fully described
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