title: Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome.
abstract: BACKGROUND
  The Björnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34-36.
  
  
  METHODS
  Refined genetic mapping and DNA sequencing of 44 genes between D2S2210 and D2S2244 revealed BCS1L mutations. Functional analyses elucidated how BCS1L mutations cause the Björnstad syndrome.
  
  
  RESULTS
  BCS1L encodes a member of the AAA family of ATPases that is necessary for the assembly of complex III in the mitochondria. In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. Patients with the Björnstad syndrome have mutations that alter residues involved in protein-protein interactions, whereas mutations in patients with complex III deficiency alter ATP-binding residues, as deduced from the crystal structure of a related AAA-family ATPase. Biochemical studies provided evidence to support this model: complex III deficiency mutations prevented ATP-dependent assembly of BCS1L-associated complexes. All mutant BCS1L proteins disrupted the assembly of complex III, reduced the activity of the mitochondrial electron-transport chain, and increased the production of reactive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species.
  
  
  CONCLUSIONS
  BCS1L mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Björnstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit for respiration in human mitochondria), but the clinical expression of the mutations was correlated with the production of reactive oxygen species. Mutations that cause the Björnstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species.
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Travis
authors.initials: JT
authors.lastname: Hinson
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.forename: Jost
authors.initials: J
authors.lastname: Schönberger
authors.forename: Noralv
authors.initials: N
authors.lastname: Breivik
authors.forename: Geir
authors.initials: G
authors.lastname: Siem
authors.forename: Barbara
authors.initials: B
authors.lastname: McDonough
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: Ivan
authors.initials: I
authors.lastname: Keogh
authors.forename: Ricardo
authors.initials: R
authors.lastname: Godinho
authors.forename: Felipe
authors.initials: F
authors.lastname: Santos
authors.forename: Alfonso
authors.initials: A
authors.lastname: Esparza
authors.forename: Yamileth
authors.initials: Y
authors.lastname: Nicolau
authors.forename: Edgar
authors.initials: E
authors.lastname: Selvaag
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Cohen
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjaerg
authors.forename: Roland D
authors.initials: RD
authors.lastname: Eavey
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D001426:Bacterial Proteins / Q000737:chemistry; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D014450:Electron Transport Complex III / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006201:Hair Diseases / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008928:Mitochondria; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D015003:Yeasts
chemical_list: C435491:BCS1L protein, human; D001426:Bacterial Proteins; C061260:RuvB protein, Bacteria; D000074183:ATPases Associated with Diverse Cellular Activities; D014450:Electron Transport Complex III