title: Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome.
abstract: Microphthalmia with linear skin defects (MLS) syndrome is an X-linked male-lethal disorder also known as MIDAS (microphthalmia, dermal aplasia, and sclerocornea). Additional clinical features include neurological and cardiac abnormalities. MLS syndrome is genetically heterogeneous given that heterozygous mutations in HCCS or COX7B have been identified in MLS-affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with MLS syndrome carry a mutation in either HCCS or COX7B. The majority of MLS-affected females have severe skewing of X chromosome inactivation, suggesting that mutations in HCCS, COX7B, and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in NDUFB11 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. NDUFB11 encodes one of 30 poorly characterized supernumerary subunits of NADH:ubiquinone oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated NDUFB11 knockdown in HeLa cells, we demonstrate that NDUFB11 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that X-linked genetic defects leading to the complete inactivation of complex I, III, or IV underlie MLS syndrome. Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of mitochondrial diseases associated with neurocutaneous manifestations.
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: van Rahden
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Erika
authors.initials: E
authors.lastname: Fernandez-Vizarra
authors.affiliation: Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Center for Bioinformatics, University of Hamburg, 20146 Hamburg, Germany; Virus Genomics Research Group, Heinrich Pette Institute-Leibniz Institute for Experimental Virology, 20246 Hamburg, Germany.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Brand
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Fellmann
authors.affiliation: Institut für Medizinische Genetik und Humangenetik, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: kkutsche@uke.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D001921:Brain / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007621:Karyotyping; D008279:Magnetic Resonance Imaging; D008850:Microphthalmos / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012868:Skin Abnormalities / Q000235:genetics* / Q000473:pathology; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C518653:NDUFB11 protein, human; D042967:Electron Transport Complex I