Abstract
The deafness-dystonia syndrome (DDS) or Mohr–Tranebjaerg syndrome (MTS, MIM 304700) is a rare X-linked recessive neurological disorder resulting from loss-of-function mutations in the nuclear DDP1/TIMM8A gene, involved in the transport and sorting of proteins to the mitochondrial inner membrane. A Mohr–Tranebjaerg patient and his mother were subjected to clinical and molecular studies. Screening of mutations were performed in TIMM8A, TIMM13, and other mitochondrial protein transport genes by conformation sensitive gel electrophoresis (CSGE), followed by direct DNA sequencing of tissue samples from the patient. Mitochondrial DNA of the patient was also sequenced at the genes for COX subunits and some mitochondrial tRNAs. Respiratory chain activities in a muscle biopsy and cultured fibroblasts from the patient were assessed using biochemical methods. mRNA expression of TIMM8A and TIMM13 was determined by RT-PCR in cultured fibroblasts. We identified a new case of Mohr–Tranebjaerg syndrome and report the characteristics of a new pathogenic de novo mutation (c.112C>T, pGln38X) in the TIMM8A gene. Biochemical measures of respiratory chain complex activities in muscle biopsy and fibroblasts did not show a major deficiency or alteration. mRNA expression studies demonstrated increased TIMM8A mRNA levels in cultured fibroblasts from the patient. Phenotypic differences among published cases seem not to be related with the mutation location or type. Our results support the idea that dysfunctions of mitochondrial protein transport, in addition to OXPHOS deficiency, can be the basis of important mitochondrial pathologies.
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Acknowledgments
We thank the patient and his mother for their collaboration in this study. The authors acknowledge the expert technical assistance of Eloísa Barber and Sonia Moliner. Dr. J.R.Blesa is an associate researcher of the Fundación Centro de Investigación Príncipe Felipe. A. Solano is a postdoctoral fellow by Fundación CIPF-Bancaixa. J.A. Prieto-Ruiz thanks the Fondo de Investigación Sanitaria (Spain) for his fellowship. This research was funded by grants of the Conselleria de Sanitat / Generalitat Valenciana (A.P. 068/06, C.Valenciana, Spain) and the Fondo de Investigación Sanitaria (FIS PI 05/2356 and FIS PI 04/1351, Spain).
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José Rafael Blesa and Abelardo Solano contributed equally to this work
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Blesa, J.R., Solano, A., Briones, P. et al. Molecular Genetics of a Patient with Mohr–Tranebjaerg Syndrome due to a New Mutation in the DDP1 Gene. Neuromol Med 9, 285–291 (2007). https://doi.org/10.1007/s12017-007-8000-3
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DOI: https://doi.org/10.1007/s12017-007-8000-3