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.

The subunit composition and function of mammalian cytochrome c oxidase

“…The authors proposed that COX7B is indispensable for COX assembly, COX activity, and mitochondrial respiration (Indrieri et al, 2012).…”

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

“…2,3 To date, only three structural subunits have been associated with disease; we reported a mutation in COX4I2 in a patient with exocrine pancreatic insufficiency, 4 Indrieri et al reported an unconventional mitochondrial disease characterized by microphthalmia with linear skin lesions caused by a COX7B defect and Massa et al described a mutation in the nuclear-encoded COX6B1 in a case of infantile encephalomyopathy. 5,6 We hereby present the second reported case of mutated COX6B1 due to a novel mutation, while expanding the clinical spectrum to include cardiomyopathy, and evaluating various therapeutic small molecules.…”

hCOA3 Stabilizes Cytochrome c Oxidase 1 (COX1) and Promotes Cytochrome c Oxidase Assembly in Human Mitochondria

“…In fact, COX deficiency is one of the most frequent causes of mitochondrial encephalomyopathies in humans (11). Mutations in the three mtDNA-encoded COX subunits and nuclear-encoded subunits COX4, COX6b, and COX7b have been identified in patients (12)(13)(14)(15)(16)(17), although these defects are relatively rare. Most COX deficiencies described to date are caused by mutations in assembly factors (8,11).…”