Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease

• Published in: American journal of human genetics 2012-11, Vol.91 (5), p.942-949
• Main Authors: INDRIERI, Alessia, VAN RAHDEN, Vanessa Alexandra, ZVULUNOV, Alex, KUTSCHE, Kerstin, ZEVIANI, Massimo, FRANCO, Brunella, TIRANTI, Valeria, MORLEO, Manuela, IACONIS, Daniela, TAMMARO, Roberta, D'AMATO, Ilaria, CONTE, Ivan, MAYSTADT, Isabelle, DEMUTH, Stephanie
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; Biological and medical sciences; Cell Line; Electron Transport Complex IV - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genes, X-Linked; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Genotype & phenotype; Humans; Lyases - genetics; Malformations of the eye; Medical genetics; Medical sciences; Microphthalmos - genetics; Microphthalmos - metabolism; Microphthalmos - pathology; Mitochondria; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Molecular and cellular biology; Molecular Sequence Data; Mutation; Ophthalmology; Oryzias - genetics; Oryzias - metabolism; Oryzias latipes; Pedigree; Phenotype; Skin; Skin - pathology; Vertebrates
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2012.09.016

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.