title: A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia.
abstract: The mitochondrial respiratory chain complex IV (cytochrome c oxidase) is a multi-subunit enzyme that transfers electrons from cytochrome c to molecular oxygen, yielding water. Its biogenesis requires concerted expression of mitochondria- and nuclear-encoded subunits and assembly factors. In this report, we describe a homozygous missense mutation in FAM36A from a patient who displays ataxia and muscle hypotonia. The FAM36A gene is a remote, putative ortholog of the fungal complex IV assembly factor COX20. Messenger RNA (mRNA) and protein co-expression analyses support the involvement of FAM36A in complex IV function in mammals. The c.154A>C mutation in the FAM36A gene, a mutation that is absent in sequenced exomes, leads to a reduced activity and lower levels of complex IV and its protein subunits. The FAM36A protein is nearly absent in patient's fibroblasts. Cells affected by the mutation accumulate subassemblies of complex IV that contain COX1 but are almost devoid of COX2 protein. We observe co-purification of FAM36A and COX2 proteins, supporting that the FAM36A defect hampers the early step of complex IV assembly at the incorporation of the COX2 subunit. Lentiviral complementation of patient's fibroblasts with wild-type FAM36A increases the complex IV activity as well as the amount of holocomplex IV and of individual subunits. These results establish the function of the human gene FAM36A/COX20 in complex IV assembly and support a causal role of the gene in complex IV deficiency.
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6500HB, The Netherlands.
authors.forename: Radek
authors.initials: R
authors.lastname: Szklarczyk
authors.forename: Bas F J
authors.initials: BF
authors.lastname: Wanschers
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Nicola
authors.initials: N
authors.lastname: Dikow
authors.forename: Mariël A M
authors.initials: MA
authors.lastname: van den Brand
authors.forename: Marthe G M
authors.initials: MG
authors.lastname: Hendriks-Franssen
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Marco
authors.initials: M
authors.lastname: Nooteboom
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.forename: Lambertus P
authors.initials: LP
authors.lastname: van den Heuvel
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D003241:Consanguinity; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D003576:Electron Transport Complex IV / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D055503:Protein Multimerization; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: C405324:Cox20 protein, S cerevisiae; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C515204:PIEZO1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D019344:Lactic Acid; D003576:Electron Transport Complex IV