{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:28:49Z","timestamp":1792794529107,"version":"4.5.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T00:00:00Z","timestamp":1566432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kidney Research UK and Northern Counties Kidney Research Fund","id":[{"id":"https:\/\/ror.org\/02gv4xy86","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Wellcome Centre for Mitochondrial Research","award":["203105\/Z\/16\/Z"],"award-info":[{"award-number":["203105\/Z\/16\/Z"]}],"id":[{"id":"https:\/\/ror.org\/03myjph80","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, Mitochondrial Disease Patient Cohort","award":["G0800674"],"award-info":[{"award-number":["G0800674"]}]},{"name":"Wellcome Trust Principal Research Fellow","award":["212219\/Z\/18\/Z"],"award-info":[{"award-number":["212219\/Z\/18\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"crossref"}]},{"name":"UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit","award":["MC_UU_00015\/9"],"award-info":[{"award-number":["MC_UU_00015\/9"]}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["GGP15041"],"award-info":[{"award-number":["GGP15041"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants include growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome), and Bj\u00f6rnstad syndrome, characterized by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems. Here we describe two patients harbouring biallelic variants in BCS1L; the first with a heterozygous variant c.166C&amp;gt;T, p.(Arg56*) together with a novel heterozygous variant c.205C&amp;gt;T, p.(Arg69Cys) and a second patient with a novel homozygous c.325C&amp;gt;T, p.(Arg109Trp) variant. The two patients presented with different phenotypes; the first patient presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. The second patient was an infant who presented with a classical GRACILE syndrome leading to death at 4\u00a0months of age. A decrease in BCS1L protein levels was seen in both patients, and biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle of both patients. A decrease in Complex III assembly was detected in the adult patient\u2019s muscle, whilst the paediatric patient displayed a combined mitochondrial respiratory chain defect in cultured fibroblasts. Yeast complementation studies indicate that the two missense variants, c.205C&amp;gt;T, p.(Arg69Cys) and c.325C&amp;gt;T, p.(Arg109Trp), impair the respiratory capacity of the cell. Together, these data support the pathogenicity of the novel BCS1L variants identified in our patients.<\/jats:p>","DOI":"10.1093\/hmg\/ddz202","type":"journal-article","created":{"date-parts":[[2019,8,15]],"date-time":"2019-08-15T15:11:12Z","timestamp":1565881872000},"page":"3766-3776","source":"Crossref","is-referenced-by-count":24,"title":["Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease"],"prefix":"10.1093","volume":"28","author":[{"given":"Monika","family":"Ol\u00e1hov\u00e1","sequence":"first","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla Ceccatelli","family":"Berti","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack J","family":"Collier","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte L","family":"Alston","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Jameson","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Trust, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon A","family":"Jones","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Trust, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel","family":"Edwards","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Langping","family":"He","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick F","family":"Chinnery","sequence":"additional","affiliation":[{"name":"Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK"},{"name":"Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Goffrini","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W","family":"Taylor","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1881-3782","authenticated-orcid":false,"given":"John A","family":"Sayer","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK"},{"name":"Renal Services, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK"},{"name":"NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne NE4 5PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,8,22]]},"reference":[{"key":"2019122822374046100_ref1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1023\/B:PRES.0000030444.52579.10","article-title":"The Q-cycle\u2014a personal perspective","volume":"80","author":"Crofts","year":"2004","journal-title":"Photosynth. Res."},{"key":"2019122822374046100_ref2","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fgene.2015.00134","article-title":"Nuclear gene mutations as the cause of mitochondrial complex III deficiency","volume":"6","author":"Fernandez-Vizarra","year":"2015","journal-title":"Front. Genet."},{"key":"2019122822374046100_ref3","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1006\/geno.1998.5580","article-title":"Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain","volume":"54","author":"Petruzzella","year":"1998","journal-title":"Genomics"},{"key":"2019122822374046100_ref4","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/S0140-6736(97)09272-6","article-title":"Iron-overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria","volume":"351","author":"Fellman","year":"1998","journal-title":"Lancet"},{"key":"2019122822374046100_ref5","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1080\/pdp.21.2.183.193","article-title":"Pathology of lethal fetal growth retardation syndrome with aminoaciduria, iron overload, and lactic acidosis (GRACILE)","volume":"21","author":"Rapola","year":"2002","journal-title":"Pediatr. Pathol. Mol. Med."},{"key":"2019122822374046100_ref6","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1086\/342773","article-title":"GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L","volume":"71","author":"Visap\u00e4\u00e4","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"2019122822374046100_ref7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/ng706","article-title":"A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure","volume":"29","author":"de Lonlay","year":"2001","journal-title":"Nat. Genet."},{"key":"2019122822374046100_ref8","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1093\/hmg\/ddm072","article-title":"Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy","volume":"16","author":"Fernandez-Vizarra","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2019122822374046100_ref9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.nmd.2008.11.016","article-title":"Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient","volume":"19","author":"Bl\u00e1zquez","year":"2009","journal-title":"Neuromuscul. Disord."},{"key":"2019122822374046100_ref10","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1056\/NEJMoa055262","article-title":"Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome","volume":"356","author":"Hinson","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"2019122822374046100_ref11","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/ajmg.a.20171","article-title":"Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene","volume":"121A","author":"De Meirleir","year":"2003","journal-title":"Am. J. Med. Genet. A"},{"key":"2019122822374046100_ref12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of disease phenotypes resulting from multilocus genomic variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. Engl. J. 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A theoretical assessment of hypotheses and proposal for future research","volume":"37","author":"Hoitzing","year":"2015","journal-title":"Bioessays"},{"key":"2019122822374046100_ref16","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/ncb2220","article-title":"During autophagy mitochondria elongate, are spared from degradation and sustain cell viability","volume":"13","author":"Gomes","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"2019122822374046100_ref17","doi-asserted-by":"crossref","first-page":"10190","DOI":"10.1073\/pnas.1107402108","article-title":"Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation","volume":"108","author":"Rambold","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2019122822374046100_ref18","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.1002\/j.1460-2075.1992.tb05474.x","article-title":"BCS1, a novel gene required for the expression of functional Rieske iron-sulfur protein in Saccharomyces cerevisiae","volume":"11","author":"Nobrega","year":"1992","journal-title":"EMBO J."},{"key":"2019122822374046100_ref19","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1006620","article-title":"Mutations in mitochondrial DNA causing tubulointerstitial kidney disease","volume":"13","author":"Connor","year":"2017","journal-title":"PLoS Genet."},{"key":"2019122822374046100_ref20","doi-asserted-by":"crossref","first-page":"487","DOI":"10.3892\/br.2017.892","article-title":"Renal manifestations of primary mitochondrial disorders","volume":"6","author":"Finsterer","year":"2017","journal-title":"Biomed. 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Mol. Genet."},{"key":"2019122822374046100_ref31","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg1903s63","article-title":"Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using polarography and spectrophotometric enzyme assays","volume":"13","author":"Barrientos","year":"2009","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"2019122822374046100_ref32","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1016\/j.bbamcr.2009.09.002","article-title":"Synthesis of cytochrome c oxidase subunit 1 is translationally downregulated in the absence of functional F1F0-ATP synthase","volume":"1793","author":"Soto","year":"2009","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddz202\/30297816\/ddz202.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/22\/3766\/31631082\/ddz202.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/22\/3766\/31631082\/ddz202.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,12,28]],"date-time":"2019-12-28T22:38:02Z","timestamp":1577572682000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/28\/22\/3766\/5552777"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,22]]},"references-count":32,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,8,22]]},"published-print":{"date-parts":[[2019,11,15]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddz202","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,11,15]]},"published":{"date-parts":[[2019,8,22]]}}}