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Human Molecular Genetics, 2002, Vol. 11, No. 5 477-486
© 2002 Oxford University Press

Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a–TIMM13 complex

Karin Roesch, Sean P. Curran, Lisbeth Tranebjaerg1 and Carla M. Koehler+

Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, CA 90095-1569, USA and 1Department of Medical Genetics, IMBG, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark

Mohr–Tranebjaerg syndrome (MTS/DFN-1) or deafness/dystonia syndrome results from a mutation in deafness/dystonia protein 1/translocase of mitochondrial inner membrane 8a (DDP1/TIMM8a). DDP1/TIMM8a is similar to a family of yeast proteins in the mitochondrial intermembrane space which mediate the import and insertion of inner membrane proteins. We now show that TIMM8a assembles in a 70 kDa complex in the intermembrane space with TIMM13. DDP1/TIMM8a is not detectable in fibroblasts derived from a patient with a missense mutation in the DDP1/TIMM8a gene; the point mutation results in cysteine-66 being changed to tryptophan-66 in the conserved ‘twin CX3C’ motif. The corresponding mutation in yeast translocase of inner membrane 8p (Tim8p) yields an unstable protein that does not assemble with yeast Tim13p. DDP1/TIMM8a, when expressed with TIMM13 in yeast mitochondria lacking the Tim8p–Tim13p complex, restores Tim23p import, and TIMM8a and TIMM13 can be cross-linked to the hTim23 import intermediate in rat and yeast mitochondria. In a similar manner to Tim8p, TIMM8a seemingly mediates the import of hTim23. Deafness/dystonia syndrome thus may be caused by decreased levels of Tim23 in the mitochondrial inner membrane in affected tissues.

+ To whom correspondence should be addressed. Tel: +1 310 794 4834; Fax: +1 310 206 4038; Email: koehler@chem.ucla.edu


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