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A Novel Mutation in NDUFB11 Unveils a New Clinical Phenotype Associated with Lactic Acidosis and Sideroblastic Anemia

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A Novel Mutation in NDUFB11 Unveils a New Clinical Phenotype Associated with Lactic Acidosis and Sideroblastic Anemia Clin Genet 2016 © 2016 John Wiley & Sons A/S. Printed in Singapore. All rights reserved Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12790 Original Article A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia a a Torraco A., Bianchi M., Verrigni D., Gelmetti V., Riley L., Niceta M., A. Torraco , M. Bianchi , Martinelli D., Montanari A., Guo Y., Rizza T., Diodato D., Di Nottia M., D. Verrignia, V. Gelmettib, , Lucarelli B., Sorrentino F., Piemonte F., Francisci S., Tartaglia M., Valente L. Rileyc d, M. Nicetae, E.M., Dionisi-Vici C., Christodoulou J., Bertini E., Carrozzo R. A novel D. Martinellif,A.Montanarig, mutation in NDUFB11 unveils a new clinical phenotype associated with Y. Guo c,T.Rizzaa,D.Diodatoa, lactic acidosis and sideroblastic anemia. M. Di Nottiaa, B. Lucarellih, Clin Genet 2016. © John Wiley & Sons A/S. Published by John Wiley & F. Sorrentino i, F. Piemontea, Sons Ltd, 2016 S. Franciscij, M. Tartagliae, NDUFB11, a component of mitochondrial complex I, is a relatively small E.M. Valentek, C. Dionisi-Vicif, integral membrane protein, belonging to the “supernumerary” group of J. Christodoulouc,d,l, subunits, but proved to be absolutely essential for the assembly of an active E. Bertinia,† and R. Carrozzoa,† complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have aUnit of Muscular and Neurodegenerative recently been discovered in association with two distinct phenotypes, i.e. Disorders, Laboratory of Molecular microphthalmia with linear skin defects and histiocytoid cardiomyopathy. Medicine, Bambino Gesù Children’s We report on a male with complex I deficiency, caused by a de novo mutation Hospital, IRCCS, Rome, Italy, in NDUFB11 and displaying early-onset sideroblastic anemia as the unique bNeurogenetics Unit, CSS-Mendel feature. This is the third report that describes a mutation in NDUFB11,but Laboratory, IRCCS Casa Sollievo della all are associated with a different phenotype. Our results further expand the Sofferenza, San Giovanni Rotondo, Italy, molecular spectrum and associated clinical phenotype of NDUFB11 defects. cGenetic Metabolic Disorders Research Unit, Children’s Hospital at Westmead, Conflictofinterest Sydney, Australia, dDiscipline of Paediatrics & Child Health, University of All authors declare that there is no conflict of interest. Sydney, Sydney, Australia, eDivision of Genetic Disorders and Rare Diseases Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy, fDivision of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy, gPasteur Institute – Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy, hStem Cell Transplant Unit, Department of Hematology and Oncology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy, iUO Talassemici -Anemie Rare del Globulo Rosso, Ospedale S Eugenio, Rome, Italy, jDepartment of Biology and Biotechnologies “C. Darwin”, Sapienza University of Rome, Rome, Italy, kSection of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy, and lDiscipline of Genetic Medicine, University of Sydney, Sydney, Australia †These authors contributed equally as senior authors. 1 Torraco et al. Key words: mitochondrial disease – NDUFB11 – OXPHOS – sideroblastic anemia Corresponding author: Rosalba Carrozzo, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, “Bambino Gesù” Children’s Hospital, IRCCS, Viale di San Paolo, 15-00146 Rome, Italy. Tel.: +39 06 685 93599 fax: +39 06 685 92024 e-mail: [email protected] Received 5 January 2016, revised and accepted for publication 18 April 2016 Mitochondrial diseases are due to a reduced capacity of de novo mutation in one female patient and an X-linked oxidative phosphorylation and, in a large proportion of inherited heterozygous 1-bp deletion in a second individ- cases, the problem can be due to a complex I defect (CI) ual, associated with histiocytoid cardiomyopathy (12). (MIM #252010) (1). The mammalian CI (NADH-CoQ NDUFB11 is a relatively small integral membrane pro- oxidoreductase) is a multisubunit complex that catalyzes tein (122 amino acids), which belongs to the “supernu- the first step in the electron transport chain, transferring merary” group of subunits, but proved to be essential for two electrons from NADH to ubiquinone coupled to the the assembly of an active complex I (11, 13). translocation of four protons across the membrane (2). We here report the clinical, biochemical, and molecular It consists of 44 subunits, thus resulting in the largest characterization of one patient with lactic acidosis, sider- enzyme of the oxidative phosphorylation (OXPHOS) oblastic anemia, and isolated defect of complex I due to system. Fourteen out of the 44 subunits constitute the a de novo three-nucleotide deletion (c.276_278delCTT) “catalytic core” (3, 4), the remaining subunits are consid- in NDUFB11 gene. ered “ancillary” subunits, and their role in the assembly, stabilization, and activity of the complex is still under active investigation, although it seems that some of them Materials and methods are absolutely essential for the assembly and stabilization Case report of an active CI (5, 6). Complex I deficiency is the most frequently observed The study was approved by the Ethical Committee of cause of OXPHOS disorders, varying widely in the the “Bambino Gesù” Children’s Hospital, Rome, Italy, severity of symptoms and clinical presentations. Typi- in agreement with the Declaration of Helsinki. Informed cal clinical presentations include cardiomyopathy, pure consent was signed by the parents of the patient. myopathy, leukoencephalopathy, hepatopathy with tubu- The patient is a boy born from healthy unrelated lopathy, and most commonly Leigh or Leigh-like syn- parents at 38 weeks of gestation by planned caesarean dromes (6–9). Hematological manifestations including delivery because a persistent fetal tachycardia was aplastic, macrocytic, or sideroblastic anemia, leukope- noticed during the last month of gestation. Oligo- nia, neutropenia, thrombocytopenia, or pancytopenia hydramnios and fetal ventricular hypertrophy were can also occur (10). Clinical phenotypes can have detected by ultrasound examination during antepartum early or delayed onset, with the former generally fol- surveillance. At birth, the baby weight was 2.9 kg and lowed by rapid progression and death within a few the heart involvement was confirmed by the finding ofan years. Due to the size of CI, the dual genetic ori- aneurysm of the fossa ovalis associated with hypertrophy gin of its subunits and the high number of ancillary of the ventricular walls with moderate trabeculature of proteins involved in its assembly, the identification of the right ventricle (interventricular septum = 5.6 mm), causative gene mutations is often challenging. Next Gen- along with mild anemia (Hb 10.4 g/dl). In the first month eration Sequencing (NGS) has been proved to be a of life, hemoglobin was low (7 g/dl) and unresponsive to powerful tool to find new genes involved in CI defect vitamin B6, B12 and folic acid. At the age of 3 months, and provide a molecular definition for undiagnosed the child was admitted to the “Bambino Gesù” Children’s patients. Hospital because of worsening of his general conditions In the last year, mutations have been discovered by and failure to thrive. Physical examination showed two different groups in NDUFB11, a gene located in mild dysmorphic features (hypertelorism, saddle nose, the short arm of the X-chromosome (Xp11.23). The low set ears), systolic murmur at the centrum of 2/6, first group described two de novo variants in two unre- hepatosplenomegaly and hydrocele. Routine blood tests lated females affected by microphthalmia with linear revealed severe anemia without a hemolytic component skin defects (11), while the second group described one (Hb: 5.9–6.3 g/dl; hematocrit: 19.0%, nv 30.00–45.00; 2 A novel mutation in NDUFB11 unveils a new clinical phenotype red blood count: 2.20 × 106 μl; MCV: 91.6 fl, nv Biochemical studies 70.00–86.00; RET%: 2.68, nv 0.20–2.00; reduced hap- Mitochondrial respiratory chain (MRC) complex activ- toglobin), metabolic acidosis (EAB 7.1 mEq/l, NaHCO3 ities were measured in muscle biopsy using a reported 17.9 mEq/l), and hyperlactacidemia (4.2–8.2 mmol/l, spectrophotometric method (14). < nv 2.1). Blood levels of vitamin B12 folates, iron Human fibroblasts were obtained from skin biop- and ferritin were in the normal range. The peripheral sies and grown in Dulbecco’s Modified Eagle Medium smear showed hypochromic red cells with anisopoik- (DMEM) supplemented with 10% fetal bovine serum, ilocytosis, and normal white blood cells morphology. 4.5 g/l glucose, and 50 μg/mL uridine. Bone marrow aspiration documented non-specific Complex V activity (in the direction of ATP synthesis) abnormalities, with a myelogram represented by 13% was measured in fibroblast mitochondria of the patient of erythroblasts with notes of dyserythropoiesis, 30% and age-matched controls, using reported spectropho- granuloblasts, 41% of mononuclear elements and 16% tometric method (15). Either succinate (the direct sub- of no-granulocyte undifferentiated elements. Virol- strate of complex II-succinate dehydrogenase), or malate ogy studies for Cytomegalovirus, Parovirus B19 and (which is utilized by malate dehydrogenase to generate Epstein–Barr virus were negative. No cytogenetic abnor- NADH, substrate of complex I-NADH dehydrogenase) malities were found.
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