A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome.
Leigh syndrome (LS) is a severe neurodegenerative disorder with characteristic bilateral lesions, typically in the brainstem and basal ganglia. It usually presents in infancy and is genetically heterogeneous, but most individuals with mitochondrial complex IV (or cytochrome c oxidase) deficiency have mutations in the biogenesis factor SURF1. We studied eight complex IV-deficient LS individuals from six families of Lebanese origin. They differed from individuals with SURF1 mutations in having seizures as a prominent feature. Complementation analysis suggested they had mutation(s) in the same gene but targeted massively parallel sequencing (MPS) of 1,034 genes encoding known mitochondrial proteins failed to identify a likely candidate. Linkage and haplotype analyses mapped the location of the gene to chromosome 19 and targeted MPS of the linkage region identified a homozygous c.3G>C (p.Met1?) mutation in C19orf79. Abolishing the initiation codon could potentially still allow initiation at a downstream methionine residue but we showed that this would not result in a functional protein. We confirmed that mutation of this gene was causative by lentiviral-mediated phenotypic correction. C19orf79 was recently renamed PET100 and predicted to encode a complex IV biogenesis factor. We showed that it is located in the mitochondrial inner membrane and forms a ∼300 kDa subcomplex with complex IV subunits. Previous proteomic analyses of mitochondria had overlooked PET100 because its small size was below the cutoff for annotating bona fide proteins. The mutation was estimated to have arisen at least 520 years ago, explaining how the families could have different religions and different geographic origins within Lebanon.
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Sze Chern
SC
Lim
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
Katherine R
KR
Smith
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
David A
DA
Stroud
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Alison G
AG
Compton
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Elena J
EJ
Tucker
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Ayan
A
Dasvarma
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3052, Australia.
Luke C
LC
Gandolfo
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Justine E
JE
Marum
Centre for Genetic Diseases, Monash Institute of Medical Research, Melbourne, VIC 3168, Australia.
Matthew
M
McKenzie
Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Heidi L
HL
Peters
Department of Medical Genetics, Sydney Children's Hospital, School of Women's and Children's Health, University of NSW, Sydney, NSW 2031, Australia.
David
D
Mowat
Department of Neurology, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Sydney, NSW 2006, Australia.
Peter G
PG
Procopis
Discipline of Paediatrics & Child Health, University of Sydney, Sydney, NSW 2006, Australia.
Bridget
B
Wilcken
Discipline of Paediatrics & Child Health, University of Sydney, Sydney, NSW 2006, Australia; Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Genetic Medicine, University of Sydney, Sydney, NSW 2006, Australia.
John
J
Christodoulou
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Garry K
GK
Brown
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
Michael T
MT
Ryan
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3052, Australia.
Melanie
M
Bahlo
Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC 3052, Australia. Electronic address: david.thorburn@mcri.edu.au.
David R
DR
Thorburn
D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D030401:Cytochrome-c Oxidase Deficiency / Q000150:complications / Q000208:ethnology* / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D018703:Founder Effect; D005816:Genetic Complementation Test; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007223:Infant; D007861:Lebanon; D007888:Leigh Disease / Q000150:complications / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics; D017422:Sequence Analysis, DNA
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C587424:PET100 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human