Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential.
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.
Bross
Peter
P
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.
Li
Zhijie
Z
Bejing Genomics Institute, Chinese Academy of Sciences, Beijing, China.|Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.
Hansen
Jakob
J
Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark.
Hansen
Jens Jacob
JJ
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.
Nielsen
Marit Nyholm
MN
Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark.
Corydon
Thomas Juhl
TJ
Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.
Georgopoulos
Costa
C
Department of Microbiology and Molecular Medicine, Centre Médical Universitaire, Geneva, Switzerland.
Ang
Debbie
D
Department of Microbiology and Molecular Medicine, Centre Médical Universitaire, Geneva, Switzerland.
Lundemose
Jytte Banner
JB
Institute of Forensic Medicine, University of Aarhus, Aarhus, Denmark.
Niezen-Koning
Klary
K
Institute for Drug Exploration (GUIDE), University Hospital Groningen and Groningen University, Groningen, The Netherlands.
Eiberg
Hans
H
Institute of Medical Genetics, Panum Institute, Copenhagen, Denmark.
Yang
Huanming
H
Bejing Genomics Institute, Chinese Academy of Sciences, Beijing, China.
Kølvraa
Steen
S
Department of Clinical Genetics, Vejle Hospital, 7100, Vejle, Denmark.
Bolund
Lars
L
Bejing Genomics Institute, Chinese Academy of Sciences, Beijing, China.|Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.
Gregersen
Niels
N
Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus University Hospital and Faculty of Health Sciences, Brendstrupgaardsvej 100, 8200, Århus N, Denmark.
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
D018835:Chaperonin 10; D018834:Chaperonin 60; D008314:Malonates; D024101:Mitochondrial Proteins; C038080:ethylmalonic acid; D044926:Butyryl-CoA Dehydrogenase