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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.
Source Information
From Harvard Medical School, Boston (J.T.H., V.R.F., J.S., B.M., I.K., A.E., Y.N., R.D.E., J.G.S., C.E.S.); the Howard Hughes Medical Institute, Boston (J.T.H., J.S., J.G.S., C.E.S.); University Hospital Würzburg and Institute of Clinical Biochemistry and Pathobiochemistry — both in Würzburg, Germany (J.S.); Aalesund Hospital, Norway (N.B., G.S.); Hammersmith Hospitals and Imperial College, London (P.S.); the Massachusetts Eye and Ear Infirmary, Boston (I.K., A.E., Y.N., R.D.E.); Instituto de Ciências Biológias e da Saúde, Pontifícia Universidade Cathólica de Minas Gerais, Belo Horizonte, Brazil (R.G.); University of Washington, Seattle (F.S.); H:S Bispebjerg Hospital, Copenhagen (E.S., L.T.); the Brain Tumor Institute, Cleveland Clinic, Cleveland (B.H.C.); Louis Stokes Veterans Affairs Medical Center, Cleveland (C.L.H.); and Institute of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen, and University Hospital of Tromsø, Tromsø, Norway (L.T.).
Drs. J.G. Seidman and C.E. Seidman contributed equally to this article.
Address reprint requests to Dr. C.E. Seidman at the Department of Genetics, Harvard Medical School, Room 256 NRB, 77 Ave. Louis Pasteur, Boston, MA 02115, or at cseidman{at}genetics.med.harvard.edu.
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