Missense Mutations in the BCSIL Gene as a Cause of the Bjornstad Syndrome  

Oleh:

Hinson, J Travis ; Fantin, Valeria R. ; Schonberger, Jost ; Breivik, Noralv ; Siem, Geir ; McDonough, Barbara ; Sharma, Pankaj ; Keogh, Ivan ; Godinho, Ricardo ; Santos, Felipe

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: The New England Journal of Medicine (keterangan: ada di Proquest) vol. 356 no. 08 (Feb. 2007), page 809.

Ketersediaan

Perpustakaan FK Nomor Panggil: N08.K.2007.01 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

BACKGROUND The Bjornstad syndrome, an autosomal recessive disorder associated with sensori- neural 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 i D2S2244 revealed BCSIL mutations. Functional analyses elucidated how BCSIL mutations cause the Bjornstad syndrome. RESULTS BCSIL encodes a member of the AAA family of ATPases that is necessary for the I assembly of complex III in the mitochondria. In addition to the Bjornstad syndrome, BCSIL mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifesta- E tions typifying severe mitochondrial disorders. Patients with the Bjornstad 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 BCSIL-associated complexes. All mu- J tant BCSIL proteins disrupted the assembly of complex III, reduced the activity of r the mitochondrial electron-transport chain, and increased the production of reac- ~ tive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species. CONCLUSIONS BCSIL mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Bjornstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCSIL 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 Bjornstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species.

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