European Journal of Pediatrics

, Volume 175, Issue 4, pp 517–525 | Cite as

A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly

  • C. B. Jackson
  • M. F. Bauer
  • A. Schaller
  • U. Kotzaeridou
  • A. Ferrarini
  • D. Hahn
  • H. Chehade
  • F. Barbey
  • C. Tran
  • S. Gallati
  • A. Haeberli
  • S. Eggimann
  • L. Bonafé
  • J-M. Nuoffer
Original Article

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.

Conclusion: Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period.

What is Known:

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.

Keywords

BCS1L Isolated complex III deficiency and assembly Mitochondrial disorder Rieske iron-sulphur protein Hypoglycaemia Glycosuria Deafness Growth retardation Fanconi syndrome Microcephaly Lactic acidosis 

Abbreviations

BCS1L

Ubiquinol-cytochrome c reductase synthesis-like gene

CS

Citrate synthase

GRACILE

Growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death syndrome

OXPHOS

Oxidative phosphorylation

RC

Respiratory chain

Supplementary material

431_2015_2661_MOESM1_ESM.doc (52 kb)
ESM 1(DOC 51 kb)
431_2015_2661_MOESM2_ESM.doc (33 kb)
ESM 2(DOC 33 kb)
431_2015_2661_MOESM3_ESM.doc (48 kb)
ESM 3(DOC 48 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • C. B. Jackson
    • 1
    • 8
  • M. F. Bauer
    • 2
  • A. Schaller
    • 3
  • U. Kotzaeridou
    • 4
  • A. Ferrarini
    • 5
  • D. Hahn
    • 1
  • H. Chehade
    • 6
  • F. Barbey
    • 7
  • C. Tran
    • 7
  • S. Gallati
    • 3
  • A. Haeberli
    • 1
  • S. Eggimann
    • 1
  • L. Bonafé
    • 7
  • J-M. Nuoffer
    • 1
  1. 1.Institute of Clinical ChemistryUniversity Hospital BerneBerneSwitzerland
  2. 2.Klinikum der Stadt LudwigshafenLudwigshafenGermany
  3. 3.Division of Human Genetics, BerneUniversity Hospital BerneBerneSwitzerland
  4. 4.Division of PediatricsHeidelbergGermany
  5. 5.Ospedale Regionale di BellinzonaBellinzonaSwitzerland
  6. 6.Pediatric Nephrology UnitCHUVLausanneSwitzerland
  7. 7.Center for Molecular DiseasesLausanne University HospitalLausanneSwitzerland
  8. 8.Research Program for Molecular Neurology, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland

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