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Mutations in CYC1, Encoding Cytochrome C1 Subunit Of View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT CYC1 c Mutations in , Encoding Cytochrome 1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia Pauline Gaignard,1,21 Minal Menezes,2,21 Manuel Schiff,3,4,5 Aure´lien Bayot,3,4 Malgorzata Rak,3,4 He´le`ne Ogier de Baulny,5 Chen-Hsien Su,6 Mylene Gilleron,7,8 Anne Lombes,7,8 Heni Abida,6 Alexander Tzagoloff,6 Lisa Riley,9 Sandra T. Cooper,2,10 Kym Mina,11,12 Padma Sivadorai,13 Mark R. Davis,13 Richard J.N. Allcock,14,15 Nina Kresoje,14 Nigel G. Laing,16,17 David R. Thorburn,18,19 Abdelhamid Slama,1 John Christodoulou,2,9,20 and Pierre Rustin3,4,* Many individuals with abnormalities of mitochondrial respiratory chain complex III remain genetically undefined. Here, we report > > CYC1 c mutations (c.288G T [p.Trp96Cys] and c.643C T [p.Leu215Phe]) in , encoding the cytochrome 1 subunit of complex III, in two unrelated children presenting with recurrent episodes of ketoacidosis and insulin-responsive hyperglycemia. Cytochrome c1, the heme-containing component of complex III, mediates the transfer of electrons from the Rieske iron-sulfur protein to cytochrome c c . Cytochrome 1 is present at reduced levels in the skeletal muscle and skin fibroblasts of affected individuals. Moreover, studies on yeast mutants and affected individuals’ fibroblasts have shown that exogenous expression of wild-type CYC1 rescues complex III activity, demonstrating the deleterious effect of each mutation on cytochrome c1 stability and complex III activity. Complex III (CIII) of the mitochondrial respiratory chain tor retardation and extrapyramidal signs, dystonia, atheto- contains 11 subunits, one of which (cytochrome b)is sis, and ataxia (from UQCRQ [MIM 615159] mutations);5 encoded by mitochondrial DNA. CIII conveys electrons mitochondrial encephalopathy (from BCS1L, TTC19 from ubiquinol to cytochrome c. It associates with com- [MIM 613814], CYTB [MIM 516020] mutations);6 pili torti plexes I (CI) and IV (CIV) to form the respirasome.1 Cyto- and sensorineural hearing loss, known as Bjo¨rnstad 7 chrome c1 (Cyt c1), cytochrome b, and the Rieske protein syndrome (from BCS1L mutations); optic neuropathy, are the three CIII redox components. The heme moiety exercise intolerance, and/or cardiomyopathy (from CYTB c 8 of Cyt 1 is in the N-terminal domain, located in the inter- mutations); and transient episodes of hypoglycemia and membrane space, where it accepts electrons from the lactic acidosis (from UQCRB [MIM 191330] and UQCRC2 9,10 Rieske protein. Cyt c1 is anchored to the phospholipid [MIM 191329] mutations). bilayer by a single C-proximal transmembrane segment.2 We first carried out respiratory chain (RC) enzyme Primary CIII deficiencies, although infrequent, have analysis of muscle, liver, and fibroblasts of two children strikingly different clinical presentations. Mutations in (from unrelated consanguineous families) presenting mitochondrial CYTB or in the nuclear genes encoding with unexplained ketoacidosis and recurrent hyperlactaci- CIII subunits or assembly factors elicit a wide range of demia. All investigations were carried out according to the tissue-specific defects in affected individuals; they include recommendations of the relevant local ethical committees encephalopathy with renal involvement or lethal infantile and with the informed consent of affected individuals hepatic failure (from BCS1L [MIM 124000] mutations in and/or their families. The study revealed an isolated CIII GRACILE syndrome [MIM 603358]);3,4 severe psychomo- deficiency in the two children (Table S1, available online). 1Laboratoire de Biochimie, Hoˆpital de Biceˆtre, Assistance Publique – Hoˆpitaux de Paris, 78 Rue du Ge´ne´ral Leclerc, 94275 Le Kremlin Biceˆtre Cedex, France; 2Discipline of Paediatrics, Sydney Medical School, University of Sydney, Camperdown NSW 2006, Australia,; 3Institut National de la Sante´ et de la Re- cherche Me´dicale Unite´ Mixte de Recherche 676, Hoˆpital Robert Debre´, 48 Boulevard Se´rurier, 75019 Paris, France; 4Faculte´ de Me´decine Denis Diderot, Universite´ Paris Diderot – Paris 7, Site Robert Debre´, 48 Boulevard Se´rurier, 75019 Paris, France; 5Reference Center for Inherited Metabolic Diseases, Hoˆpital Robert Debre´, Assistance Publique – Hoˆpitaux de Paris, 48 Boulevard Se´rurier, 75019 Paris, France; 6Department of Biological Sciences, Columbia University, New York, NY 10027, USA; 7Institut National de la Sante´ et de la Recherche Me´dicale Unite´ Mixte de Recherche 1016, Institut Cochin, 75014 Paris, France; 8Service de Biochimie Me´tabolique et Centre de Ge´ne´tique Mole´culaire et Chromosomique, Hoˆpital de La Salpeˆtrie`re, Assistance Publique – Hoˆpitaux de Paris, 75651 Paris, France; 9Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children’s Hospital at Westmead, Sydney, Westmead NSW 2145, Australia; 10Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Sydney, Westmead NSW 2145, Australia; 11Department of Molecular Genetics, PathWest Laboratory Medicine WA, Royal Perth Hospital, Perth, WA 6000, Australia; 12School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, WA 6009, Australia; 13Neurogenetic Laboratory, Department of Anatomical Pathology, PathWest Laboratory Medicine WA, Royal Perth Hospital, Perth, WA 6000, Australia; 14Lotterywest State Biomedical Facility Genomics and School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA 6009, Australia; 15Department of Clinical Immunology, PathWest Laboratory Medicine WA, Royal Perth Hospital, Perth, WA 6000, Australia; 16Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia; 17Western Australian Institute for Medical Research, Queen Elizabeth II Medical Centre, Nedlands, WA 6009, Australia; 18Victorian Clinical Genetics Services, Murdoch Childrens Research Institute and Royal Children’s Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia; 19Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia; 20Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia 21These authors contributed equally to this work *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ajhg.2013.06.015. Ó2013 by The American Society of Human Genetics. All rights reserved. 384 The American Journal of Human Genetics 93, 384–389, August 8, 2013 Figure 1. Gene Analysis in Families Affected by CYC1 Mutations (A) Pedigrees of the Lebanese (with P1) and Sri Lankan (with P2) families. Affected individuals (dark symbols) harbor homozygous (À/À) mutations. Unaffected individuals are either heterozygous (À/þ) or wild-type (þ/þ). (B) Analysis of CYC1 genomic DNA. For P1, a single candidate disease-causing homozygous missense variant in CYC1 was identified by exome sequencing. For P2, who has defective CIII activity, a candidate-gene strategy resulted in sequencing cDNA obtained from total RNA of cultured fibroblasts and revealed a missense mutation (c.643C>T) in CYC1. c (C and D) Cyt 1 structures (C) and alignment (D). The first child (P1; II-3, Lebanese family in Figure 1)is episodes of fulminant lactic acidemia with intercurrent the son of first-cousin parents of Lebanese background. illnesses; his lactate-to-pyruvate ratio was as high as 66, An older brother has autism and intellectual disability, and his blood glucose was labile (it fluctuated from 3 to and an older sister and a younger brother exhibit normal 30 mmol/l) and required insulin therapy. This prompted growth and development. The proband was born at us to investigate RC enzyme in muscle, liver, and skin 36 weeks of gestation (Table S2) after a pregnancy compli- biopsies, which revealed a severe and consistent isolated cated by gestational diabetes, for which his mother needed CIII defect (the ratio of CIII to citrate synthase activity insulin therapy. His birth weight was 2,300 g (10–50th was 4%, 24,% and 25% of the mean control values in liver, percentile), his length was 46 cm (10–50th percentile), muscle, and skin fibroblasts, respectively) (Table S1). At and his head circumference was 32 cm (50–90th percen- 34 months of age, he was exhibiting normal development tile). He had normal early development. He first presented and was assessed to have normal cardiac, ophthalmolog- at 5 months of age with severe metabolic ketoacidosis (pH ical, and audiological functions. His weight was 11.2 kg 7.04) after a 24 hr history of a febrile illness causing (first percentile), and his length was 86.5 cm (first percen- vomiting (Table S1). His initial blood lactate was tile). His head circumference 6 months earlier was 48.0 cm 13 mmol/l (normal range ¼ 0.7–2.0 mmol/l), and he also (23rd percentile). had hyperammonemia (260 mmol/l; normal range ¼ 10– The second affected child (P2; II-3, Sri Lankan family in 50 mmol/l). He was treated with fluid resuscitation, sodium Figure 1) is a girl (third child) born to first-cousin parents benzoate, and arginine, and over the next few days his of Sri Lankan background. After an uneventful pregnancy biochemistry corrected. He went on to have recurrent and delivery, she presented with mild growth retardation The American Journal of Human Genetics 93, 384–389, August 8, 2013 385 and congenital left ptosis. She was admitted at 2.5 years of of For the Sri Lankan girl (P2), who has low CIII activity in age for acute vomiting with
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