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      Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

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      1 , 2 , 3 , 4 , 4 , 4 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 3 , 5 , 6 , 7 , 4 , 2 , 4 , 1 , 4 , 1 , 2 , 2 , 8 , 9 , 1 , 2 , 8
      Cold Spring Harbor Molecular Case Studies
      Cold Spring Harbor Laboratory Press
      asymmetric, linear skin defects, dilated cardiomyopathy, left ventricular noncompaction cardiomyopathy, linear hyperpigmentation, microphthalmos, oncocytic cardiomyopathy, ventricular fibrillation, Wolff–Parkinson–White syndrome

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          Abstract

          Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).

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          Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease.

          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. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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            Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.

            The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations--a missense mutation (p.R217C) and a nonsense mutation (p.R197X)--in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c-type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c(1). We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal-truncated Delta 197-268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c-type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c-mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS.
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              Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome.

              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.
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                Author and article information

                Journal
                Cold Spring Harb Mol Case Stud
                Cold Spring Harb Mol Case Stud
                cshmcs
                cshmcs
                cshmcs
                Cold Spring Harbor Molecular Case Studies
                Cold Spring Harbor Laboratory Press
                2373-2873
                January 2017
                : 3
                : 1
                : a001271
                Affiliations
                [1 ]NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom;
                [2 ]National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom;
                [3 ]Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, BT9 7AB, United Kingdom;
                [4 ]Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom;
                [5 ]Department of Clinical Genetics, Laboratory Medicine, The Queen Elizabeth University Hospital, Glasgow G51 4TF, United Kingdom;
                [6 ]Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom;
                [7 ]Histopathology Department, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom;
                [8 ]MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
                [9 ]National Heart Centre Singapore, Singapore 169609, Singapore
                Author notes
                [10]

                Joint senior authors

                Article
                ReaMCS001271
                10.1101/mcs.a001271
                5171697
                c4372cb3-4be3-4519-bff9-7206615569b5
                © 2017 Rea et al.; Published by Cold Spring Harbor Laboratory Press

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted reuse and redistribution provided that the original author and source are credited.

                History
                : 6 July 2016
                : 20 October 2016
                Page count
                Pages: 11
                Funding
                Funded by: Academy of Medical Sciences http://dx.doi.org/10.13039/501100000691
                Funded by: Wellcome Trust http://dx.doi.org/10.13039/100004440
                Funded by: British Heart Foundation http://dx.doi.org/10.13039/501100000274
                Funded by: Arthritis Research UK http://dx.doi.org/10.13039/501100000341
                Funded by: National Institute for Health Research (NIHR) http://dx.doi.org/10.13039/501100000272
                Funded by: Biomedical Research Unit in Cardiovascular Disease
                Funded by: Royal Brompton
                Funded by: Harefield NHS Foundation Trust
                Funded by: Imperial College London
                Funded by: Medical Research Council (UK) http://dx.doi.org/10.13039/501100000265
                Funded by: Foundation Leducq
                Funded by: Health Innovation Challenge Fund (HICF)
                Funded by: Wellcome Trust http://dx.doi.org/10.13039/100004440
                Funded by: The Lily Foundation
                Funded by: UK NHS Highly Specialised Commissioners
                Categories
                Research Report

                asymmetric, linear skin defects,dilated cardiomyopathy,left ventricular noncompaction cardiomyopathy,linear hyperpigmentation,microphthalmos,oncocytic cardiomyopathy,ventricular fibrillation,wolff–parkinson–white syndrome

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