title: A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly.
abstract: We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood.
  
  
  CONCLUSIONS
  Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period.
  
  
  BACKGROUND
  • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.
authors.affiliation: Institute of Clinical Chemistry, University Hospital Berne, Berne, Switzerland. christopher.jackson@helsinki.fi.|Research Program for Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. christopher.jackson@helsinki.fi.
authors.forename: C B
authors.identifier: http://orcid.org/0000-0003-1035-6417
authors.initials: CB
authors.lastname: Jackson
authors.affiliation: Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany.
authors.forename: M F
authors.initials: MF
authors.lastname: Bauer
authors.affiliation: Division of Human Genetics, Berne, University Hospital Berne, Berne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Schaller
authors.affiliation: Division of Pediatrics, Heidelberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Kotzaeridou
authors.affiliation: Ospedale Regionale di Bellinzona, Bellinzona, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Ferrarini
authors.affiliation: Institute of Clinical Chemistry, University Hospital Berne, Berne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Hahn
authors.affiliation: Pediatric Nephrology Unit, CHUV, Lausanne, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Chehade
authors.affiliation: Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Barbey
authors.affiliation: Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Tran
authors.affiliation: Division of Human Genetics, Berne, University Hospital Berne, Berne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Gallati
authors.affiliation: Institute of Clinical Chemistry, University Hospital Berne, Berne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Haeberli
authors.affiliation: Institute of Clinical Chemistry, University Hospital Berne, Berne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Eggimann
authors.affiliation: Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Bonafé
authors.affiliation: Institute of Clinical Chemistry, University Hospital Berne, Berne, Switzerland.
authors.forename: J-M
authors.initials: JM
authors.lastname: Nuoffer
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000140:Acidosis, Lactic / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002779:Cholestasis / Q000235:genetics*; D003638:Deafness / Q000235:genetics*; D003937:Diagnosis, Differential; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005198:Fanconi Syndrome / Q000209:etiology / Q000235:genetics*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics; D006486:Hemosiderosis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000151:congenital* / Q000235:genetics; D020125:Mutation, Missense; D000608:Renal Aminoacidurias / Q000235:genetics*
chemical_list: C435491:BCS1L protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D014450:Electron Transport Complex III
keywords: BCS1L; Deafness; Fanconi syndrome; Glycosuria; Growth retardation; Hypoglycaemia; Isolated complex III deficiency and assembly; Lactic acidosis; Microcephaly; Mitochondrial disorder; Rieske iron-sulphur protein