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• W2997372293 abstract "Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies. Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies. Complex III (CIII, also called ubiquinol:cytochrome c oxidoreductase or bc1 complex) is an electron transfer enzyme complex; it is the component of the mitochondrial respiratory chain that transports electrons from ubiquinol to cytochrome c. This redox reaction is coupled to proton translocation from the mitochondrial matrix to the intermembrane space via the “Q-cycle,” contributing to the proton gradient required for ATP synthesis.1Crofts A.R. Holland J.T. Victoria D. Kolling D.R.J. Dikanov S.A. Gilbreth R. Lhee S. Kuras R. Kuras M.G. The Q-cycle reviewed: How well does a monomeric mechanism of the bc(1) complex account for the function of a dimeric complex?.Biochim. Biophys. Acta. 2008; 1777: 1001-1019Crossref PubMed Scopus (95) Google Scholar Mammalian CIII possesses a symmetrical dimeric structure (CIII2) in which each monomer is composed of 10 different subunits.2Iwata S. Lee J.W. Okada K. Lee J.K. Iwata M. Rasmussen B. Link T.A. Ramaswamy S. Jap B.K. Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex.Science. 1998; 281: 64-71Crossref PubMed Scopus (1003) Google Scholar, 3Xia D. Esser L. Tang W.-K. Zhou F. Zhou Y. Yu L. Yu C.-A. Structural analysis of cytochrome bc1 complexes: implications to the mechanism of function.Biochim. Biophys. Acta. 2013; 1827: 1278-1294Crossref PubMed Scopus (85) Google Scholar, 4Smith P.M. Fox J.L. Winge D.R. Reprint of: Biogenesis of the cytochrome bc(1) complex and role of assembly factors.Biochim. Biophys. Acta. 2012; 1817: 872-882Crossref PubMed Scopus (13) Google Scholar Three of those subunits are catalytic and possess electron transfer properties: CYB, CYC1, and UQCRFS1, whose intermembrane-space-facing C terminus contains an iron-sulfur (2Fe-2S) cluster. UQCRFS1 is synthesized as a pre-protein in the cytosol, and its import into the mitochondrial matrix is directed by its cleavable N-terminal mitochondrial targeting sequence (MTS). Following import, UQCRFS1 is stabilized by the chaperone LYRM7.5Sánchez E. Lobo T. Fox J.L. Zeviani M. Winge D.R. Fernández-Vizarra E. LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of mitochondrial Complex III assembly in human cells.Biochim. Biophys. Acta. 2013; 1827: 285-293Crossref PubMed Scopus (54) Google Scholar,6Invernizzi F. Tigano M. Dallabona C. Donnini C. Ferrero I. Cremonte M. Ghezzi D. Lamperti C. Zeviani M. A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.Hum. Mutat. 2013; 34: 1619-1622Crossref PubMed Scopus (42) Google Scholar Direct binding of the co-chaperone HSC20 to LYRM7 is required for recruitment of the 2Fe-2S transfer complex to the LYRM7-UQCRFS1 intermediate, and ultimately for 2Fe-2S cluster incorporation into UQCRFS1.7Maio N. Kim K.S. Singh A. Rouault T.A. A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.Cell Metab. 2017; 25: 945-953.e6Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Once UQCRFS1 has acquired its 2Fe-2S cluster, BCS1L translocates and incorporates it into the pre-CIII2 complex, rendering it catalytically active.8Nobrega F.G. Nobrega M.P. Tzagoloff A. BCS1, a novel gene required for the expression of functional Rieske iron-sulfur protein in Saccharomyces cerevisiae.EMBO J. 1992; 11: 3821-3829Crossref PubMed Scopus (134) Google Scholar,9Fernandez-Vizarra E. Zeviani M. Mitochondrial complex III Rieske Fe-S protein processing and assembly.Cell Cycle. 2018; 17: 681-687Crossref PubMed Scopus (19) Google Scholar Interestingly, cleavage of the UQCRFS1 MTS is carried out only after its incorporation into CIII2.7Maio N. Kim K.S. Singh A. Rouault T.A. A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.Cell Metab. 2017; 25: 945-953.e6Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Although crystal structures from bovine heart CIII revealed the presence of UQCRFS1 N-terminal-derived peptides in between the core subunits UQCRC1 and UQCRC2,2Iwata S. Lee J.W. Okada K. Lee J.K. Iwata M. Rasmussen B. Link T.A. Ramaswamy S. Jap B.K. Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex.Science. 1998; 281: 64-71Crossref PubMed Scopus (1003) Google Scholar,9Fernandez-Vizarra E. Zeviani M. Mitochondrial complex III Rieske Fe-S protein processing and assembly.Cell Cycle. 2018; 17: 681-687Crossref PubMed Scopus (19) Google Scholar,10Brandt U. Yu L. Yu C.A. Trumpower B.L. The mitochondrial targeting presequence of the Rieske iron-sulfur protein is processed in a single step after insertion into the cytochrome bc1 complex in mammals and retained as a subunit in the complex.J. Biol. Chem. 1993; 268: 8387-8390Abstract Full Text PDF PubMed Google Scholar later research showed that their prominent accumulation in the absence of TTC19 would be detrimental to CIII function.11Bottani E. Cerutti R. Harbour M.E. Ravaglia S. Dogan S.A. Giordano C. Fearnley I.M. D’Amati G. Viscomi C. Fernandez-Vizarra E. Zeviani M. TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III.Mol. Cell. 2017; 67: 96-105.e4Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Hence the current assumption is that during its incorporation, UQCRFS1 is processed in situ, and several peptides containing its MTS remain bound to CIII2. Later, these peptides have to be removed to preserve CIII2 structural integrity and function. This process is facilitated by TTC19.9Fernandez-Vizarra E. Zeviani M. Mitochondrial complex III Rieske Fe-S protein processing and assembly.Cell Cycle. 2018; 17: 681-687Crossref PubMed Scopus (19) Google Scholar,11Bottani E. Cerutti R. Harbour M.E. Ravaglia S. Dogan S.A. Giordano C. Fearnley I.M. D’Amati G. Viscomi C. Fernandez-Vizarra E. Zeviani M. TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III.Mol. Cell. 2017; 67: 96-105.e4Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar The functional importance of this turnover still needs to be elucidated, especially in the context of different metabolic demands.9Fernandez-Vizarra E. Zeviani M. Mitochondrial complex III Rieske Fe-S protein processing and assembly.Cell Cycle. 2018; 17: 681-687Crossref PubMed Scopus (19) Google Scholar Within the mitochondrial respiratory chain, CIII2 is forming supercomplexes together with Complex I (CI) and Complex IV (CIV), and the most abundant of these supercomplexes (CI1III2IV1) is termed “respirasome.”12Gu J. Wu M. Guo R. Yan K. Lei J. Gao N. Yang M. The architecture of the mammalian respirasome.Nature. 2016; 537: 639-643Crossref PubMed Scopus (177) Google Scholar, 13Letts J.A. Fiedorczuk K. Sazanov L.A. The architecture of respiratory supercomplexes.Nature. 2016; 537: 644-648Crossref PubMed Scopus (256) Google Scholar, 14Wu M. Gu J. Guo R. Huang Y. Yang M. Structure of Mammalian Respiratory Supercomplex I1III2IV1.Cell. 2016; 167: 1598-1609.e10Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar Isolated CIII deficiencies are among the least frequently diagnosed mitochondrial disorders. They are associated with heterogeneous clinical presentations.15Bénit P. Lebon S. Rustin P. Respiratory-chain diseases related to complex III deficiency.Biochim. Biophys. Acta. 2009; 1793: 181-185Crossref PubMed Scopus (70) Google Scholar, 16Meunier B. Fisher N. Ransac S. Mazat J.-P. Brasseur G. Respiratory complex III dysfunction in humans and the use of yeast as a model organism to study mitochondrial myopathy and associated diseases.Biochim. Biophys. Acta. 2013; 1827: 1346-1361Crossref PubMed Scopus (33) Google Scholar, 17Fernández-Vizarra E. Zeviani M. Nuclear gene mutations as the cause of mitochondrial complex III deficiency.Front. Genet. 2015; 6: 134Crossref PubMed Scopus (71) Google Scholar To date, mutations in genes encoding five subunits, MT-CYB (MIM: 516020),18Andreu A.L. Hanna M.G. Reichmann H. Bruno C. Penn A.S. Tanji K. Pallotti F. Iwata S. Bonilla E. Lach B. et al.Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA.N. Engl. J. Med. 1999; 341: 1037-1044Crossref PubMed Scopus (337) Google Scholar,19Schuelke M. Krude H. Finckh B. Mayatepek E. Janssen A. Schmelz M. Trefz F. Trijbels F. Smeitink J. Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation.Ann. Neurol. 2002; 51: 388-392Crossref PubMed Scopus (64) Google Scholar CYC1 (MIM: 615453),20Gaignard P. Menezes M. Schiff M. Bayot A. Rak M. Ogier de Baulny H. Su C.-H. Gilleron M. Lombes A. Abida H. et al.Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia.Am. J. Hum. Genet. 2013; 93: 384-389Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar UQCRC2 (MIM: 191329),21Miyake N. Yano S. Sakai C. Hatakeyama H. Matsushima Y. Shiina M. Watanabe Y. Bartley J. Abdenur J.E. Wang R.Y. et al.Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation.Hum. Mutat. 2013; 34: 446-452Crossref PubMed Scopus (55) Google Scholar UQCRB (MIM: 19330),22Haut S. Brivet M. Touati G. Rustin P. Lebon S. Garcia-Cazorla A. Saudubray J.M. Boutron A. Legrand A. Slama A. A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis.Hum. Genet. 2003; 113: 118-122Crossref PubMed Scopus (116) Google Scholar and UQCRQ (MIM: 612080),23Barel O. Shorer Z. Flusser H. Ofir R. Narkis G. Finer G. Shalev H. Nasasra A. Saada A. Birk O.S. Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ.Am. J. Hum. Genet. 2008; 82: 1211-1216Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar and five assembly factors, UQCC2 (MIM: 614461),24Tucker E.J. Wanschers B.F.J. Szklarczyk R. Mountford H.S. Wijeyeratne X.W. van den Brand M.A.M. Leenders A.M. Rodenburg R.J. Reljić B. Compton A.G. et al.Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression.PLoS Genet. 2013; 9: e1004034Crossref PubMed Scopus (61) Google Scholar,25Feichtinger R.G. Brunner-Krainz M. Alhaddad B. Wortmann S.B. Kovacs-Nagy R. Stojakovic T. Erwa W. Resch B. Windischhofer W. Verheyen S. et al.Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.Oxid. Med. Cell. Longev. 2017; 2017: 7202589Crossref PubMed Scopus (23) Google Scholar UQCC3 (MIM: 616097),26Wanschers B.F.J. Szklarczyk R. van den Brand M.A.M. Jonckheere A. Suijskens J. Smeets R. Rodenburg R.J. Stephan K. Helland I.B. Elkamil A. et al.A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability.Hum. Mol. Genet. 2014; 23: 6356-6365Crossref PubMed Scopus (42) Google Scholar LYRM7 (MIM: 615838),6Invernizzi F. Tigano M. Dallabona C. Donnini C. Ferrero I. Cremonte M. Ghezzi D. Lamperti C. Zeviani M. A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.Hum. Mutat. 2013; 34: 1619-1622Crossref PubMed Scopus (42) Google Scholar BCS1L (MIM: 124000, 603358, and 262000),27de Lonlay P. Valnot I. Barrientos A. Gorbatyuk M. Tzagoloff A. Taanman J.W. Benayoun E. Chrétien D. Kadhom N. Lombès A. et al.A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.Nat. Genet. 2001; 29: 57-60Crossref PubMed Scopus (242) Google Scholar, 28Visapää I. Fellman V. Vesa J. Dasvarma A. Hutton J.L. Kumar V. Payne G.S. Makarow M. Van Coster R. Taylor R.W. et al.GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L.Am. J. Hum. Genet. 2002; 71: 863-876Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 29Hinson J.T. Fantin V.R. Schönberger J. Breivik N. Siem G. McDonough B. Sharma P. Keogh I. Godinho R. Santos F. et al.Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome.N. Engl. J. Med. 2007; 356: 809-819Crossref PubMed Scopus (146) Google Scholar and TTC19 (MIM: 615157),30Ghezzi D. Arzuffi P. Zordan M. Da Re C. Lamperti C. Benna C. D’Adamo P. Diodato D. Costa R. Mariotti C. et al.Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies.Nat. Genet. 2011; 43: 259-263Crossref PubMed Scopus (108) Google Scholar have been reported in more than 140 individuals.25Feichtinger R.G. Brunner-Krainz M. Alhaddad B. Wortmann S.B. Kovacs-Nagy R. Stojakovic T. Erwa W. Resch B. Windischhofer W. Verheyen S. et al.Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.Oxid. Med. Cell. Longev. 2017; 2017: 7202589Crossref PubMed Scopus (23) Google Scholar With more than 50 published cases, the most frequent causes of CIII deficiency are variants in MT-CYB, typically associated with myopathy and exercise intolerance. This is followed by more than 30 cases with variants in BCS1L that are associated with either Björnstad syndrome or GRACILE syndrome.17Fernández-Vizarra E. Zeviani M. Nuclear gene mutations as the cause of mitochondrial complex III deficiency.Front. Genet. 2015; 6: 134Crossref PubMed Scopus (71) Google Scholar,25Feichtinger R.G. Brunner-Krainz M. Alhaddad B. Wortmann S.B. Kovacs-Nagy R. Stojakovic T. Erwa W. Resch B. Windischhofer W. Verheyen S. et al.Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.Oxid. Med. Cell. Longev. 2017; 2017: 7202589Crossref PubMed Scopus (23) Google Scholar Both of these syndromes are severe neurologic and multi-systemic diseases with neonatal onset. Similar phenotypes have been reported in individuals with pathogenic variants in UQCRB, UQCRC2, and CYC1, who presented with neonatal or early infantile onset, recurrent metabolic crises with elevated lactate levels and hypoglycemia, from which they completely and quickly recovered with intravenous glucose. All but one showed normal development and intellect.25Feichtinger R.G. Brunner-Krainz M. Alhaddad B. Wortmann S.B. Kovacs-Nagy R. Stojakovic T. Erwa W. Resch B. Windischhofer W. Verheyen S. et al.Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.Oxid. Med. Cell. Longev. 2017; 2017: 7202589Crossref PubMed Scopus (23) Google Scholar Based solely on clinical presentation, it is impossible to distinguish between subunit or assembly factor defects. All reported affected individuals are following an autosomal recessive mode of inheritance, apart from those with pathogenic variants in the mitochondrial DNA (mtDNA)-encoded MT-CYB that are maternally inherited or occur spontaneously. CIII defects, with the exception of TTC19 deficiency, often present as combined respiratory chain deficiencies in combination with CI and, in some cases, with CIV deficiencies.24Tucker E.J. Wanschers B.F.J. Szklarczyk R. Mountford H.S. Wijeyeratne X.W. van den Brand M.A.M. Leenders A.M. Rodenburg R.J. Reljić B. Compton A.G. et al.Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression.PLoS Genet. 2013; 9: e1004034Crossref PubMed Scopus (61) Google Scholar,31Morán M. Marín-Buera L. Gil-Borlado M.C. Rivera H. Blázquez A. Seneca S. Vázquez-López M. Arenas J. Martín M.A. Ugalde C. Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency.Hum. Mutat. 2010; 31: 930-941Crossref PubMed Scopus (47) Google Scholar One reason could be the formation of supercomplexes, in which the presence of fully assembled CIII would be a prerequisite for the stability or assembly of CI and CIV.25Feichtinger R.G. Brunner-Krainz M. Alhaddad B. Wortmann S.B. Kovacs-Nagy R. Stojakovic T. Erwa W. Resch B. Windischhofer W. Verheyen S. et al.Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.Oxid. Med. Cell. Longev. 2017; 2017: 7202589Crossref PubMed Scopus (23) Google Scholar,32Ghezzi D. Zeviani M. Human diseases associated with defects in assembly of OXPHOS complexes.Essays Biochem. 2018; 62: 271-286Crossref PubMed Scopus (35) Google Scholar In this study, we report the clinical and molecular findings of two unrelated children with CIII deficiency, lactic acidosis, fetal bradycardia, lactic acidosis, hypertrophic cardiomyopathy, and alopecia totalis (Table 1). We recruited both individuals from the German network for mitochondrial disorders (MitoNET). Their parents provided written informed consent for all aspects of the study and for publication of facial photographs according to the Declaration of Helsinki. The ethical committees of both participating centers (Charité EA2/107/14 and TU Munich 5360/12S) have approved the study.Table 1Clinical Phenotypes of Both Probands Encoded According to the Human Phenotype Ontology (HPO)Characteristics and SymptomsHPO IDProband 1Proband 2Mutation in UQCRFS1 (NM_006003)NAhomozygous c.215-1G>Cc.41T>A | c.610C>TEffect on translation (NP_005994)NAp.Val72_Thr81del10p.Val14Asp | p.Arg204∗OriginNAAfghanistanGermanyGenderNAmalemaleAge at onsetNAcongenitalcongenitalAge at last assessmentNA3.5 months9 yearsAge at deathNA3.5 monthsNAFetal DevelopmentIntrauterine growth retardation (<P10)HP:0001511-+Low birth weightHP:0001518- (59th percentile)+ (3rd percentile)Fetal bradycardiaHP:0001662++Perinatal DevelopmentPersistent fetal circulationHP:0011726ND+HypothermiaHP:0002045+NDFeeding difficultiesHP:0008872++HyperventilationHP:0002883+NDMetabolismLactic acidosis [highest level]HP:000312824 mmol/l15 mmol/lMetabolic crises during febrile infectionsHP:0004897ND+Cardiovascular SystemHypertrophic cardiomyopathyHP:0001639++Ventricular septal defectHP:0001629-+Persistent left superior vena cavaHP:0005301-+Pericardial effusionHP:0001698+NDMotor SystemMuscular hypotoniaHP:0001252(+)+Muscular weaknessHP:0001324++Delayed motor developmentHP:0001270ND+Elevated creatine kinase levels [highest]HP:0003236>5,000 U/lNDHematologic SystemThrombocytopeniaHP:0001873(+)+Normochromic anemiaHP:0001895ND+Abnormality of blood coagulationHP:0001928+NDVisual SystemBilateral papilledemaHP:0001085ND+Skin and AppendagesAlopecia totalisHP:0007418++Gastrointestinal SystemCholelithiasisHP:0001081+NDNA—not applicable, ND—not done or no information available Open table in a new tab NA—not applicable, ND—not done or no information available The male proband 1 (P1, Figure 1) was the first child of consanguineous Afghan parents, born at term by emergency Caesarean section due to fetal bradycardia. At the first day of life, physicians noted hypothermia, borderline thrombocytopenia (152/nL; N > 150), lactic acidosis (24 mmol/l; N < 2.0), and elevated creatine kinase levels (>5.000 IU/l; N < 190). Skin and skeletal muscle biopsies were performed on the first day of life. Measurements of respiratory chain enzyme activities showed normal values in the muscle and low-normal values in skin fibroblasts for combined CII+III activity (Tables S1 and S2). Metabolic urine tests revealed increased excretion of ketone bodies and of lactate. Plasma alanine was markedly elevated. Thiamine and coenzyme Q10 supplementation was initiated. Electroencephalogram (EEG) showed slightly pathologic baseline activity initially, but EEG results were normal at 7 weeks of age. Neonatal screening revealed hearing impairment. Echocardiography at the first day of life showed septum and right ventricle hypertrophy, increased right-ventricular pressure (≈65% of systemic pressure), and a patent ductus arteriosus with bi-directional shunting. At day 13, hypertrophic cardiomyopathy had progressed in severity and was treated with metoprolol. Echocardiography at age 2 months showed reduced biventricular function with severe ventricular hypertrophy. The size of the left ventricular posterior wall was 6–7 mm (Z score +5.3), and the left ventricular outflow tract was obstructed (Vmax of 2.9 m/s). Although P1 was born with scalp hair, 8 weeks after birth, his scalp hair had been lost entirely (Figure 1). P1 deceased at the age of 3.5 months from severe hypertrophic cardiomyopathy. Proband 2 (P2, Figure 1) is a male and the youngest child of healthy unrelated German parents. An elder brother is healthy. During pregnancy, fetal growth retardation and a persistent left upper vena cava were diagnosed. He was born at 37 weeks of gestation by Caesarean section due to fetal bradycardia. Postnatal complications arose from hypertrophic cardiomyopathy, ventricular septum defect (VSD), persistent fetal circulation, and lactic acidosis, as well as thrombocytopenia and severe normochromic anemia. During early infancy, feeding difficulties, muscular hypotonia, and a moderately delayed psychomotor development became evident. Febrile infections triggered a series of more than 10 severe metabolic crises with high lactate levels of up to 15 mmol/l (N 0.5–2.2). Under normal conditions, serum lactate levels were within the reference range. Cranial MRI performed at the ages of 6 months and 5 years did not reveal any abnormality, especially no signs for Leigh syndrome (Figure 1). Subsequently, the boy‘s condition stabilized, and he was able to walk independently at 23 months of age, while language and cognitive development were adequate for his age. Both VSD and persistent fetal circulation resolved spontaneously in the first year of life while the hypertrophic cardiomyopathy remained stable without impairment of cardiac function. Normocytic anemia with blood hemoglobin of 6.25 mmol/l (N 7.4–9.1) and thrombocytopenia with 178/nL (N 285–510) are persistent, but do not require therapeutic intervention. Assessment of cultured skin fibroblasts revealed isolated CIII deficiency (Table S3). At birth, P2 had very fine and curly hair of the scalp, which he lost entirely during early infancy. Since then, he has total alopecia of the scalp with very fine and sparse hair intermittently growing only to be lost again. In contrast, his eyelashes and eyebrows are present (Figure 1). Microscopic hair analysis did not reveal any abnormalities. At 5 years of age, bilateral papilledema was diagnosed despite normal cerebrospinal fluid pressure (13 cm H2O) and without visual impairment. After initiation of Coenzyme Q10 supplementation with 8 mg/kg BW at the age of 6 years, the boy has remained in a good health for the last 3 years, without any further metabolic crises and with improved exercise tolerance. He displays slightly impaired gross and fine motor skills. His general muscle strength is reduced, but his walking ability in the plain is normal. The clinical phenotypes of both probands using the Human Phenotype Ontology33Groza T. Köhler S. Moldenhauer D. Vasilevsky N. Baynam G. Zemojtel T. Schriml L.M. Kibbe W.A. Schofield P.N. Beck T. et al.The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease.Am. J. Hum. Genet. 2015; 97: 111-124Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar terms are described on Table 1. In order to elucidate the genetic cause of the disease, we performed whole-exome sequencing (WES) on blood cell genomic DNA from both probands. This was done independently at the Institute of Human Genetics, Technical University Munich and at the NeuroCure Clinical Research Center, Charité–Universitätsmedizin Berlin, as described.34Schottmann G. Seelow D. Seifert F. Morales-Gonzalez S. Gill E. von Au K. von Moers A. Stenzel W. Schuelke M. Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.Neurol. Genet. 2015; 1: e32Crossref PubMed Scopus (17) Google Scholar,35Kremer L.S. Bader D.M. Mertes C. Kopajtich R. Pichler G. Iuso A. Haack T.B. Graf E. Schwarzmayr T. Terrile C. et al.Genetic diagnosis of Mendelian disorders via RNA sequencing.Nat. Commun. 2017; 8: 15824Crossref PubMed Scopus (202) Google Scholar Later, both groups connected via GeneMatcher.36Sobreira N. Schiettecatte F. Valle D. Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene.Hum. Mutat. 2015; 36: 928-930Crossref PubMed Scopus (594) Google Scholar Clinical and biochemical data suggested a mitochondrial disorder with the autosomal recessive mode of inheritance. In P1, WES failed to identify likely pathogenic variants in genes associated with mitochondrial disease, but it did reveal a rare, potentially pathogenic homozygous splice-acceptor-site variant in UQCRFS1 (chr19:g.29,699,066C>G [GRCh37.p11] | c.215-1G>C [RefSeq accession number NM_006003.2]; Figure 2) as the only mitochondrial protein candidate gene.37Elstner M. Andreoli C. Klopstock T. Meitinger T. Prokisch H. Chapter 1: The Mitochondrial Proteome Database: MitoP2.in: Methods in Enzymology. Academic Press, 2009: 3-20Google Scholar Segregation analysis via Sanger sequencing identified both parents as heterozygous carriers of this splice-site variant. To investigate the effect of this splice-site variant on the transcript level, we performed splicing analysis via RT-PCR and subsequent Sanger sequencing. This revealed a splicing defect resulting in the activation of a cryptic downstream splice-site and an in-frame deletion of 30 nucleotides and thus of 10 amino acids at a highly conserved region of the protein (Figure 2). In P2, after assessing the pathogenic potential of variants with MutationTaster2,38Schwarz J.M. Cooper D.N. Schuelke M. Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age.Nat. Methods. 2014; 11: 361-362Crossref PubMed Scopus (1959) Google Scholar we identified two heterozygous UQCRFS1 variants (chr19:g.29,703,985A>T [GRCh37.p11] | c.41T>A [RefSeq NM_006003.2] | [p.Val14Asp] [RefSeq NP_005994.2] and chr19:g.29,698,670G>A | c.610C>T | [p.Arg204∗]; Figure 2). Segregation analysis via Sanger sequencing showed the c.41T>A variant to be inherited from the mother and the c.610C>T variant from the father. His elder sibling was also tested and discovered to be heterozygous for the c.610C>T variant only. RT-PCR verified that the c.610C>T mutant transcript evaded nonsense-mediated mRNA messenger (NMD) decay (Figure S1) because the premature termination codon (PTC) was located within 3′ of the last exon-exon boundary.39Thermann R. Neu-Yilik G. Deters A. Frede U. Wehr K. Hagemeier C. Hentze M.W. Kulozik A.E. Binary specification of nonsense codons by splicing and cytoplasmic translation.EMBO J. 1998; 17: 3484-3494Crossref PubMed Scopus (321) Google Scholar No additional predicted pathogenic variants were detected for P2 in virtual gene panels for muscle diseases (n = 337 genes) and alopecia (n = 62 genes) (see Supplemental Information). Bioinformatic analysis of p.Val14Asp on the TargetP-2.0 Server40Emanuelsson O. Brunak S. von Heijne G. Nielsen H. Locating proteins in the cell" @default.
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• W2997372293 title "Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis" @default.
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