Effects of a Mutation in the HSPE1 Gene Encoding the Mitochondrial Co-chaperonin HSP10 and Its Potential Association with a Neurological and Developmental Disorder

Research output: Research - peer-reviewJournal article

DOI

  • Anne S Bie
    Anne S Bie
  • Paula Fernandez-Guerra
  • Rune I D Birkler
    Rune I D Birkler
  • Shahar Nisemblat
    Shahar NisemblatDepartment of Biochemistry & Molecular Biology, Tel Aviv University Tel Aviv, Israel.
  • Dita Pelnena
    Dita Pelnena
  • Xinping Lu
    Xinping LuDepartment of Biochemistry & Molecular Biology, Tel Aviv University Tel Aviv, Israel.
  • Joshua L Deignan
    Joshua L DeignanDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles Los Angeles, CA, USA.
  • Hane Lee
    Hane LeeDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles Los Angeles, CA, USA.
  • Naghmeh Dorrani
    Naghmeh DorraniDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los AngelesLos Angeles, CA, USA; Department of Pediatrics, David Geffen School of Medicine at University of California, Los AngelesLos Angeles, CA, USA.
  • Thomas J Corydon
  • Johan Palmfeldt
  • Liga Bivina
    Liga BivinaDivision of Genomic Medicine, Department of Pediatrics, UC Davis Health System Sacramento, CA, USA.
  • Abdussalam Azem
    Abdussalam AzemDepartment of Biochemistry & Molecular Biology, Tel Aviv University Tel Aviv, Israel.
  • Kristin Herman
    Kristin HermanDivision of Genomic Medicine, Department of Pediatrics, UC Davis Health System Sacramento, CA, USA.
  • Peter Bross

We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature. To evaluate whether the mutation may be disease-associated we investigated its effects by in vitro and ex vivo studies. Our in vitro studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although, we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient.

Original languageEnglish
JournalFrontiers in Molecular Biosciences
Volume3
Pages (from-to)65
ISSN2296-889X
DOIs
StatePublished - 2016

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