title: Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential.
abstract: Molecular chaperones assist protein folding, and variations in their encoding genes may be disease-causing in themselves or influence the phenotypic expression of disease-associated or susceptibility-conferring variations in many different genes. We have screened three candidate patient groups for variations in the HSPD1 and HSPE1 genes encoding the mitochondrial Hsp60/Hsp10 chaperone complex: two patients with multiple mitochondrial enzyme deficiency, 61 sudden infant death syndrome cases (MIM: #272120), and 60 patients presenting with ethylmalonic aciduria carrying non-synonymous susceptibility variations in the ACADS gene (MIM: *606885 and #201470). Besides previously reported variations we detected six novel variations: two in the bidirectional promoter region, and one synonymous and three non-synonymous variations in the HSPD1 coding region. One of the non-synonymous variations was polymorphic in patient and control samples, and the rare variations were each only found in single patients and absent in 100 control chromosomes. Functional investigation of the effects of the variations in the promoter region and the non-synonymous variations in the coding region indicated that none of them had a significant impact. Taken together, our data argue against the notion that the chaperonin genes play a major role in the investigated diseases. However, the described variations may represent genetic modifiers with subtle effects.
authors.affiliation: Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark. Peter.Bross@ki.au.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Bross
authors.affiliation: Bejing Genomics Institute, Chinese Academy of Sciences, Beijing, China.|Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Li
authors.affiliation: Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark.|Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: Jens Jacob
authors.initials: JJ
authors.lastname: Hansen
authors.affiliation: Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark.
authors.forename: Marit Nyholm
authors.initials: MN
authors.lastname: Nielsen
authors.affiliation: Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: Thomas Juhl
authors.initials: TJ
authors.lastname: Corydon
authors.affiliation: Department of Microbiology and Molecular Medicine, Centre Médical Universitaire, Geneva, Switzerland.
authors.forename: Costa
authors.initials: C
authors.lastname: Georgopoulos
authors.affiliation: Department of Microbiology and Molecular Medicine, Centre Médical Universitaire, Geneva, Switzerland.
authors.forename: Debbie
authors.initials: D
authors.lastname: Ang
authors.affiliation: Institute of Forensic Medicine, University of Aarhus, Aarhus, Denmark.
authors.forename: Jytte Banner
authors.initials: JB
authors.lastname: Lundemose
authors.affiliation: Institute for Drug Exploration (GUIDE), University Hospital Groningen and Groningen University, Groningen, The Netherlands.
authors.forename: Klary
authors.initials: K
authors.lastname: Niezen-Koning
authors.affiliation: Institute of Medical Genetics, Panum Institute, Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.affiliation: Bejing Genomics Institute, Chinese Academy of Sciences, Beijing, China.
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Clinical Genetics, Vejle Hospital, 7100, Vejle, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Kølvraa
authors.affiliation: Bejing Genomics Institute, Chinese Academy of Sciences, Beijing, China.|Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Bolund
authors.affiliation: Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
mesh_terms: D044926:Butyryl-CoA Dehydrogenase / Q000235:genetics; D018835:Chaperonin 10 / Q000235:genetics*; D018834:Chaperonin 60 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008314:Malonates / Q000378:metabolism / Q000652:urine; D024101:Mitochondrial Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013398:Sudden Infant Death / Q000235:genetics
chemical_list: D018835:Chaperonin 10; D018834:Chaperonin 60; D008314:Malonates; D024101:Mitochondrial Proteins; C038080:ethylmalonic acid; D044926:Butyryl-CoA Dehydrogenase