title: Effects of a Mutation in theHSPE1Gene Encoding the Mitochondrial Co-chaperonin HSP10 and Its Potential Association with a Neurological and Developmental Disorder.
abstract: We here report molecular investigations of a missense mutation in theHSPE1gene 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 aHSPE1NM_002157.2:c.217C>Tde novomutation 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 byin vitroandex vivostudies. Ourin vitrostudies 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.
authors: Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital Aarhus, Denmark.
authors: Anne S
authors: AS
authors: Bie
authors: Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital Aarhus, Denmark.
authors: Paula
authors: P
authors: Fernandez-Guerra
authors: Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital Aarhus, Denmark.
authors: Rune I D
authors: RI
authors: Birkler
authors: Department of Biochemistry & Molecular Biology, Tel Aviv University Tel Aviv, Israel.
authors: Shahar
authors: S
authors: Nisemblat
authors: Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital Aarhus, Denmark.
authors: Dita
authors: D
authors: Pelnena
authors: Department of Biochemistry & Molecular Biology, Tel Aviv University Tel Aviv, Israel.
authors: Xinping
authors: X
authors: Lu
authors: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles Los Angeles, CA, USA.
authors: Joshua L
authors: JL
authors: Deignan
authors: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles Los Angeles, CA, USA.
authors: Hane
authors: H
authors: Lee
authors: Department 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.
authors: Naghmeh
authors: N
authors: Dorrani
authors: Department of Biomedicine, Aarhus University Aarhus, Denmark.
authors: Thomas J
authors: TJ
authors: Corydon
authors: Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital Aarhus, Denmark.
authors: Johan
authors: J
authors: Palmfeldt
authors: Division of Genomic Medicine, Department of Pediatrics, UC Davis Health System Sacramento, CA, USA.
authors: Liga
authors: L
authors: Bivina
authors: Department of Biochemistry & Molecular Biology, Tel Aviv University Tel Aviv, Israel.
authors: Abdussalam
authors: A
authors: Azem
authors: Division of Genomic Medicine, Department of Pediatrics, UC Davis Health System Sacramento, CA, USA.
authors: Kristin
authors: K
authors: Herman
authors: Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital Aarhus, Denmark.
authors: Peter
authors: P
authors: Bross
keywords: De novo mutations; mitochondrial proteins; molecular chaperones; neurological disorders; oxidative stress; protein folding