title: Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease.
abstract: Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). Unlike other mitochondrial diseases, MLS is characterized by a well-recognizable neurodevelopmental phenotype. Interestingly, not all clinically diagnosed MLS cases have mutations in HCCS, thus suggesting genetic heterogeneity for this disorder. Among the possible candidates, we analyzed the X-linked COX7B and found deleterious de novo mutations in two simplex cases and a nonsense mutation, which segregates with the disease, in a familial case. COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase (COX), the MRC complex IV. We demonstrated that COX7B is indispensable for COX assembly, COX activity, and mitochondrial respiration. Downregulation of the COX7B ortholog (cox7B) in medaka (Oryzias latipes) resulted in microcephaly and microphthalmia that recapitulated the MLS phenotype and demonstrated an essential function of complex IV activity in vertebrate CNS development. Our results indicate an evolutionary conserved role of the MRC complexes III and IV for the proper development of the CNS in vertebrates and uncover a group of mitochondrial diseases hallmarked by a developmental phenotype.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Indrieri
authors.forename: Vanessa Alexandra
authors.initials: VA
authors.lastname: van Rahden
authors.forename: Valeria
authors.initials: V
authors.lastname: Tiranti
authors.forename: Manuela
authors.initials: M
authors.lastname: Morleo
authors.forename: Daniela
authors.initials: D
authors.lastname: Iaconis
authors.forename: Roberta
authors.initials: R
authors.lastname: Tammaro
authors.forename: Ilaria
authors.initials: I
authors.lastname: D'Amato
authors.forename: Ivan
authors.initials: I
authors.lastname: Conte
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.forename: Stephanie
authors.initials: S
authors.lastname: Demuth
authors.forename: Alex
authors.initials: A
authors.lastname: Zvulunov
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Brunella
authors.initials: B
authors.lastname: Franco
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003576:Electron Transport Complex IV / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D050172:Genes, X-Linked; D005838:Genotype; D006801:Humans; D008190:Lyases / Q000235:genetics; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009990:Oryzias / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000473:pathology
chemical_list: C496843:COX7B protein, human; D003576:Electron Transport Complex IV; D008190:Lyases; C031581:cytochrome C synthetase