title: A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency.
abstract: Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Oláhová
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jessica Ac
authors.initials: JA
authors.lastname: Houghton
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Andrew Am
authors.initials: AA
authors.lastname: Morris
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford, UK.
authors.forename: Garry K
authors.initials: GK
authors.lastname: Brown
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Zofia Ma
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Lightowlers
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics*; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D024101:Mitochondrial Proteins; C587424:PET100 protein, human