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Mitochondrial Diseases Caused by Mutations in Inner Membrane Chaperone Proteins

  • Lisbeth Tranebjærg
Chapter

Abstract

This chapter summarizes current knowledge of several disorders associated with the dysfunction of the mitochondrial membrane chaperone proteins, and pays particular attention to the X-linked recessive Mohr–Tranebjaerg syndrome (MTS), also called deafness-dystonia-optic neuronopathy syndrome (DDON syndrome), caused by mutations in TIMM8A.

The human disorders associated with mutations in the chaperone genes present clinically with extremely different phenotypes. Even within MTS, there is considerable variability of clinical symptoms. However, some characteristic clinical abnormalities include early-onset profound hearing impairment, dystonia, later occurrence of optic atrophy of cerebral origin (optic neuronopathy), and often serious personality changes with loss of inhibition and cognitive decline. In addition, the majority of patients have some degree of learning disability during childhood. Neuropathological abnormalities include general brain atrophy, particularly of visual cortex, with histological examinations of temporal bones showing a complete loss of neurons with relative preservation of other components of the auditory pathways, typical of auditory neuropathy. Although MTS is an X-linked disorder which is more often observed in males, affected females have also been described.

The mechanisms leading to neurodegeneration in MTS do not correlate to abnormal oxidative phosphorylation (OXPHOS) function, but there is recent evidence for morphologically abnormal mitochondria in fibroblasts from patients. Much more research is needed to understand the pathology. MTS should be suspected in males with hearing impairment and dystonia, but should also be considered in females with the appropriate clinical symptoms.

Keywords

Deafblindness TIMM8A Mitochondrial Neurodegeneration Syndrome 

Notes

Acknowledgments

Some of the work took place at the Wilhelm Johannsen Center for Functional Genome Research, established by the Danish National Research Foundation. We acknowledge thefinancial support to the project by the Lundbeck Foundation, grant R9-A918. The data compiled here are the result of dedicated collaborative work and inspiring discussions since the 1990s involving many people: Marijke van Ghelue, Mona Nystad, Department of medical Genetics, University Hospital of Northern Norway, N-Tromsø, Norway; David Scheie, Department of Pathology, University Hospital, Oslo, Norway; Marianne Lodahl and Nanna Dahl Rendtorff, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Denmark.

We would like to acknowledge and thank the colleagues allowing us to briefly mention unpublished MTS patients: Mary Ellen Conley, MD, West Research Tower, LeBonHeur Children’s Hospital, Memphis TN; Dirk Kunst, Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, the Netherlands; Irene Stolte-Dijkstra, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Alain Verloes, M.D., Ph.D, Department of Genetics, Robert Debre Hospital, Referring Centre for developmental abnormalities and syndromic malformations, Paris, France; John Tolmie, and Katherine McWilliams, Clinical Genetics, Ferguson-Smith Centre, Glasgow, Scotland; Miles Humberstones, MD, Department of Neurology, Nottingham University Hospital, Nottingham, UK; Jan Ulrik Prause, MD, PhD, Department of Eye Pathology, University of Copenhagen, Denmark; Henning Laursen, MD,PhD; Department of Neuropathology, University Hospital of Copenhagen, Denmark; Saumil Merchant, MD, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA; Kirsty Gardner-Berry, BSc, Department of Audiology, SCIC, Gladesville Hospital, Gladesville, NSW, Australia; Graham Reynolds, MD, Department of Paediatrics and Child Health, ANU Medical School, Canberra Hospital, Australia; Melanie Wong, Department of Allergy and Immunology, Children’s Hospital, Westmead, NSW, Australia.

References

  1. 1.
    Christian BE, Spremulli LL (2011) Mechanism of protein biosynthesis in mammalian mitochondria. Biochim Biophys Acta. Epub 7 Dec 2011Google Scholar
  2. 2.
    DiMauro S, Davidzon G (2005) Mitochondrial DNA and disease. Ann Med 37:222–232PubMedCrossRefGoogle Scholar
  3. 3.
    Rötig A (2011) Human diseases with impaired mitochondrial protein synthesis. Biochim Biophys Acta 1807(9):1198–1205PubMedCrossRefGoogle Scholar
  4. 4.
    Calvo SE, Mootha VK (2010) The mitochondrial proteome and human disease. Annu Rev Genomics Genet 11:25–44CrossRefGoogle Scholar
  5. 5.
    Kutik S, Guiard B, Meyer HE, Wiedemann N, Pfanner N (2007) Cooperation of translocase complexes in mitochondrial protein import. J Cell Biol 179(4):585–591PubMedCrossRefGoogle Scholar
  6. 6.
    Mokranjac D, Neupert W (2010) The many faces of the mitochondrial TIN23 complex. Biochim et Biophys Acta 1797:1045–1054CrossRefGoogle Scholar
  7. 7.
    Bauer MF, Neupert W (2001) Import of proteins into mitochondria: a novel pathomechanism for progressive neurodegeneration. J Inher Metab Dis 24:166–180PubMedCrossRefGoogle Scholar
  8. 8.
    Mokranjac D, Neupert W (2009) Thirty years of protein translocation into mitochondria: Unexpectedly complex and still puzzling. Biochim et Biophys Acta 1793:33–41CrossRefGoogle Scholar
  9. 9.
    Beverly KN, Sawaya MR, Schmid E, Koehler CM (2008) The Tim8-Tim13 complex has multiple substrate binding sites and binds cooperatively to Tim23. J Mol Biol 382(5):1144–1156PubMedCrossRefGoogle Scholar
  10. 10.
    Tranebjaerg L, Hamel BC, Gabreels FJ, Renier WO, Van Ghelue M (2000a) A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome. Eur J Hum Genet 8:464–467CrossRefGoogle Scholar
  11. 11.
    Kirby DM, Thorburn DR (2008) Approaches to finding the molecular basis of mitochondrial oxidative phosphorylation disorders. Twin Res Hum Genet 11:395–411PubMedCrossRefGoogle Scholar
  12. 12.
    Scharfe C, Lu HH, Neuenburg JK, Allen EA, Li GC, Klopstock T, Cowan TM, Enns GM, Davis RWl (2009) Mapping gene associations in human mitochondria using clinical disease phenotypes. PLoS Comput Biol 5(4):e1000374Google Scholar
  13. 13.
    Lieber DS, Vafai SB, Horton LC, Slate NG, Liu S, Borowsky ML, Calvo SE, Schmahmann JD, Mootha VK (2012) Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease. BMC Med Genet 13:3Google Scholar
  14. 14.
    Polke JM, Laurá M, Pareyson D, Taroni F, Milani M, Bergamin G, Gibbons VS, Houlden H, Chamley SC, Blake J, DeVile C, Sandford R, Sweeney MG, Davis MB, Reilly MM (2011) Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations. Neurology 77:168–173PubMedCrossRefGoogle Scholar
  15. 15.
    Rouzier C, Bannwarth S, Chaussenot A, Chevrollier A, verschueren A, Bonello-Palot N, Fragaki K, Cano A, Pouget J, Pellisier JF, Procaccio V, Chabrol B, Paguis-Flucklinger V (2012) The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy ‘plus’ phenotype. Brain 135(Pt 1):23–34PubMedCrossRefGoogle Scholar
  16. 16.
    Frank S (2006) Dysregulation of mitochondrial fusion and fission: an emerging concept in neurodegeneration. Arch neuropathol 111(2):93–100CrossRefGoogle Scholar
  17. 17.
    Chen H, Chan DC (2005) Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet 14(2):R283–R289PubMedCrossRefGoogle Scholar
  18. 18.
    Elachouri G, Vidoni S, Zanna C, Pattyn A, Boukhaddaoui H, Gaget K, Yu-Wai-Man P, Gasparre G, Sarzi E, Delettre C, Olichon A, Loiseau D, Reynier P, Chinnery PF, Rotig A, Carelli V, Hamel CP, Rugolo M, Lenaers G (2011) OPA1 links human mitochondrial genome to mtDNA replication and distribution. Genome Res 21(1):12–20PubMedCrossRefGoogle Scholar
  19. 19.
    Ahting U, Floss T, Uez N, Schneider-Lohmar I, Becker L, Kling E, Iuso A, bender A, de Angelis MH, Gailus-Durner V, Fuchs H, Meitinger T, Wurst W, Prokisch H, Klopstock T (2009) Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import. Biochiim et Biophys Acta 1787:371–376CrossRefGoogle Scholar
  20. 20.
    Mackenzie JA, Payne RM (2007) Mitochondrial protein import and human health and disease. Biochim et Biophysica Acta 1772:509–523CrossRefGoogle Scholar
  21. 21.
    Jin H, Kendall E, Freeman TC, Roberts RG, Vetrie DLP (1999) The human family of deafness/dystonia peptide (DDP) related mitochondrial import proteins. Genomics 61:259–267PubMedCrossRefGoogle Scholar
  22. 22.
    Davey KM, Parboosingh JS, McLeod DR, Chan R, Casey R, Ferreira P, Snyder FF, Bridge PJ, bernier FP (2006) Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J Med Genet 43:385–393PubMedCrossRefGoogle Scholar
  23. 23.
    Shridhar V, Bible J, Staub R, Avula R, Lee YK, Kalli K, Huang H, Hartmann LC, Kaufmann SH, Smith DI (2001) Loss of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer. Cancer Res 61:4258–4265PubMedGoogle Scholar
  24. 24.
    Lindsey JC, Lusher ME, Strathdee G, Brown R, Gilbertson RJ, Bailey S, Ellison DW, Clifford SC (2006) Epigenetic inactivation of MCJ (DNAJD1) in malignant paediatric brain tumours. Int J Cancer 118:346–352PubMedCrossRefGoogle Scholar
  25. 25.
    Badenkop RF, Cherian S, Lord RSA, Baysal BE, Taschner PEM, Schofield PR (2001) Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromoso Cancer 31:255–263CrossRefGoogle Scholar
  26. 26.
    Tranebjaerg L, Schwartz C, Eriksen H, Andreasson S, Ponjavic V, Dahl A, Stevenson RE, May M, Arena F, Barker D, Elverland HH, Lubs H (1995) A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. J Med Genet 32:257–263PubMedCrossRefGoogle Scholar
  27. 27.
    Mohr J, Mageroy K (1960) Sex-linked deafness of a possibly new type. Acta Genet Stat Med 10:54–62PubMedGoogle Scholar
  28. 28.
    Vetrie D et al (1993) The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature 361:226–233PubMedCrossRefGoogle Scholar
  29. 29.
    Jin H, May M, Tranebjaerg L, Kendall E, Fontan G, Jackson J, Subramony SH, Arena F, Lubs H, Smith S, Stevenson R, Schwartz C, Vetrie D (1996) A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. Nat Genet 14:177–180PubMedCrossRefGoogle Scholar
  30. 30.
    Koehler CM, Leuenberger D, Merchant S, Renold A, Junne T, Schatz G (1999) Human deafness dystonia syndrome is a mitochondrial disease. Proc Natl Acad Sci U S A 96:2141–2146PubMedCrossRefGoogle Scholar
  31. 31.
    Tranebjærg L (2009) Deafness-dystonia-optic neuronopathy syndrome. In: Pagon RA, Bird TD, Dolan CR et al (eds) Gene reviews. www.genetests.org. Accessed 29 July 2012Google Scholar
  32. 32.
    Jensen PK (1981) Nerve deafness: optic nerve atrophy, and dementia: a new X-linked recessive syndrome? Am J Med Genet 9:55–60PubMedCrossRefGoogle Scholar
  33. 33.
    Jensen PK, Reske-Nielsen E, Hein-Sorensen O, Warburg M (1987) The syndrome of opticoacoustic nerve atrophy with dementia. Am J Med Genet 28:517–518PubMedCrossRefGoogle Scholar
  34. 34.
    Tranebjaerg L, Van Ghelue M, Nilssen O, Hodes ME, Dlouhy SR, Farlow MR, Hamel B, Arts WFM, Jankovic J, Beach J, Jensen PKA (1997) Jensen syndrome is allelic to Mohr-Tranebjaerg syndrome and both are caused by mutations in the DDP gene. Am J Hum Genet 61S:A349Google Scholar
  35. 35.
    Tranebjaerg L, Jensen PK, van Ghelue M (2000b) X-linked recessive deafness-dystonia syndrome (Mohr-Tranebjaerg syndrome). Adv Otorhinolaryngol 56:176–180CrossRefGoogle Scholar
  36. 36.
    Tranebjaerg L, Jensen PK, Van Ghelue M, Vnencak-Jones CL, Sund S, Elgjo K, Jakobsen J, Lindal S, Warburg M, Fuglsang-Frederiksen A, Skullerud K (2001) Neuronal cell death in the visual cortex is a prominent feature of the X-linked recessive mitochondrial deafness-dystonia syndrome caused by mutations in the TIMM8a gene. Ophthalmic Genet 22:207–223PubMedCrossRefGoogle Scholar
  37. 37.
    Koeppen AH (2011) Friedreiach’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci 303(1–2):1–12PubMedCrossRefGoogle Scholar
  38. 38.
    Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, DiMauro S, Thorburn DR, Mootha VK (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Trans Med 4(118):118ra10Google Scholar
  39. 39.
    Merchant SN, McKenna MJ, Nadol JB, Kristiansen AG, Tropitzsch A, Lindal S, Tranebjaerg L (2001) Temporal bone histopathologic and genetic studies in Mohr-Tranebjaerg syndrome (DFN-1). Otol Neurotol 22:506–511PubMedCrossRefGoogle Scholar
  40. 40.
    Bahmad F Jr, Merchant SN, Nadol JB Jr, Tranebjaerg L (2007) Otopathology in Mohr-Tranebjaerg syndrome. Laryngoscope 117:1202–1208PubMedCrossRefGoogle Scholar
  41. 41.
    Brookes JT, Kanis AB, Tan LY, Tranebjaerg L, Vore A, Smith RJ (2007) Cochlear implantation in deafness-dystonia-optic neuronopathy (DDON) syndrome. Int J Pediatr Otorhinolaryngol 72:121–126PubMedCrossRefGoogle Scholar
  42. 42.
    Richter D, Conley ME, Rohrer J, Myers LA, Zahradka K, Kelecic J, Sertic J, Stavljenic-Rukavina A (2001) A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. Pediatr Allergy Immunol 12:107–111PubMedCrossRefGoogle Scholar
  43. 43.
    Sedivá A, Smith CI, Asplund AC, Hadac J, Janda A, Zeman J, Hansíková H, Dvoráková L, Mrázová L, Velbri S, Koehler C, Roesch K, Sullivan KE, Futatani T, Ochs HD (2007) Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. J Clin Immunol 27:640–646PubMedCrossRefGoogle Scholar
  44. 44.
    Arai T, Zhao M, Kanegane H, van Zelm MC, Futatani T, Yamada M, Ariga T, Ochs HD, Miyawaki T, Oh-ishi T (2011) Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes. J Hum Genet 56(8): 577–582PubMedCrossRefGoogle Scholar
  45. 45.
    Aguirre LA, Pérez-Bas M, Villamar M, Barcena JE, López-Ariztegui MA, Moreno-Pelayo MA, Moreno F, del Castillo I (2008) A Spanish sporadic case of deafness-dystonia (Mohr-Tranebjaerg) syndrome with a novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes. Neuromuscular Disorders 16:979–981CrossRefGoogle Scholar
  46. 46.
    Aguirre LA, del Castillo I, Macaya A, Meda C, Villamar M, Moreno-Pelayo MA, Moreno F (2006) A novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes, in a Spanish familial case of deafness-dystonia (Mohr-Tranebjaerg) syndrome. Am J Med Genet A 140:392–397PubMedGoogle Scholar
  47. 47.
    Varga RJ, Lewis R, Kimberling WJ (2002) Auditory neuropathy in a family with Mohr-Tranebjaerg syndrome due to a nonsense mutation in TIMM8a. Am J Hum Genet 71:A2006Google Scholar
  48. 48.
    Cacase AT, Pinheiro JM (2011) The mitochondrial connection in auditory neuropathy. Audiol Neurotol 16(6):398–413CrossRefGoogle Scholar
  49. 49.
    Ha AD, Parratt KL, Rendtorff ND, Lodahl M, Ng K, Rowe DB, Sue CM, Morris JG, Hayes MW, Tranebjaerg L, Fung VSC (2012) The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome. Mov Disord (in press)Google Scholar
  50. 50.
    Blesa JR, Solano A, Briones P, Prieto-Ruiz JA, Hernandez-Yago J, Coria F (2007) Molecular genetics of a patient with Mohr-Tranebjaerg syndrome due to a new mutation in the DDP1 gene. Neuromol Med 9:285–291CrossRefGoogle Scholar
  51. 51.
    Binder J, Hofmann S, Kreisel S, Wohrle JC, Bazner H, Krauss JK, Hennerici MG, Bauer MF (2003) Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene. Brain 126:1814–1820PubMedCrossRefGoogle Scholar
  52. 52.
    Ponjavic V, Andreasson S, Tranebjaerg L, Lubs HA (1996) Full-field electroretinograms in a family with Mohr-Tranebjaerg syndrome. Acta Ophthalmol Scand 74:632–635PubMedCrossRefGoogle Scholar
  53. 53.
    Williams PA, Morgan JE, Votruba M (2010) Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy. Brain 133:2942–2951PubMedCrossRefGoogle Scholar
  54. 54.
    Carelli V, Morgia CL, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA (2009) Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim et Biophys Acta 1787:518–528CrossRefGoogle Scholar
  55. 55.
    Reske-Nielsen E, Jensen PK, Hein-Sørensen O, Abelskov K (1988) Calcification of the central nervous system in a new hereditary neurological syndrome. Acta Neuropathol 75:590–596PubMedCrossRefGoogle Scholar
  56. 56.
    Scribanu N, Kennedy C (1976) Familial syndrome with dystonia, neural deafness, and possible intellectual impairment: clinical course and pathological findings. Adv Neurol 14:235–243PubMedGoogle Scholar
  57. 57.
    Conley ME, Howard VC (1993) X-linked agammaglobulinemia (2011). In: www.genetests.org, Pagon RA, Bird TD, Dolan CR et al (eds) Gene reviews. University of Washington, Seattle (WA)Google Scholar
  58. 58.
    Conley ME, Rohrer J, Minegishi Y (2000) X-linked agammaglobulinemia. Clin Rev Allergy Immunol 19:183–204PubMedCrossRefGoogle Scholar
  59. 59.
    Rendtorff ND, Lodahl M, Boulahbel H, Johansen IR, Pandya A, Welch KO, Norris VW, Arnos KS, Bitner-Glindzicz M, Emery SB, Mets MB, Fagerheim T, Eriksson K, Hansen L, Bruhn H, Möller C, Lindholm S, Ensgård S, Lesperance MM, Tranebjærg L (2011) Missense mutations in WFS1 cause autosomal dominant inherited optic atrophy and hearing loss in eight families. Am J Med Genet 155(6):1298–1313CrossRefGoogle Scholar
  60. 60.
    Meyer E, Michaelides M, Tree LJ, Robson AG, Rahman F, Pasha S, Luxon LM, Moore AT, Maher ER (2010) Nonsense mutation in TMEM126A causing autosomal recessive optic atrophy and auditory neuropathy. Mol Vis 16: 650–664PubMedGoogle Scholar
  61. 61.
    Pizzuti A, Fabbrini G, Salehi L, Vacca L, Inghilleri M, Dallapiccola B, Berardelli A (2004) Focal dystonia caused by Mohr-Tranebjaerg syndrome with complete deletion of the DDP1 gene. Neurology 62:1021–1022PubMedCrossRefGoogle Scholar
  62. 62.
    Ujike H, Tanabe Y, Takehisa Y, Hayabara T, Kuroda S (2001) A family with X-linked dystonia-deafness syndrome with a novel mutation of the DDP gene. Arch Neurol 58:1004–1007PubMedCrossRefGoogle Scholar
  63. 63.
    Swerdlow RH, Wooten GF (2001) A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome. Ann Neurol 50:537–540PubMedCrossRefGoogle Scholar
  64. 64.
    Swerdlow RH, Juel VC, Wooten GF (2004) Dystonia with and without deafness is caused by TIMM8A mutation. In: Fahn S, Hallett M, Mahlon R (eds) Dystonia 4: advances in neurology, vol 94. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  65. 65.
    Plenge RM, Tranebjaerg L, Jensen PK, Schwartz C, Willard HF (1999) Evidence that mutations in the X-linked DDP gene cause incompletely penetrant and variable skewed X inactivation. Am J Hum Genet 64:759–767PubMedCrossRefGoogle Scholar
  66. 66.
    Orstavik KH, Orstavik RE, Eiklid K, Tranebjaerg L (1996) Inheritance of skewed X chromosome inactivation in a large family with X-linked recessive deafness syndrome. Am J Med Genet 64:31–34PubMedCrossRefGoogle Scholar
  67. 67.
    Kreisel SH, Binder J, Wohrle JC, Krauss JK, Hofmann S, Bauer MF, Hennerici MG, Bazner H (2004) Dystonia in the Mohr-Tranebjaerg syndrome responds to GABAergic substances. Mov Disord 19:1241–1243PubMedCrossRefGoogle Scholar
  68. 68.
    Hayes MW, Ouvrier RA, Evans W, Somerville E, Morris JG (1998) X-linked dystonia-deafness syndrome. Mov Disord 13:303–308PubMedCrossRefGoogle Scholar
  69. 69.
    Ezquerra M, Campdelacreu J, Munoz E, Tolosa E, Marti MJ (2005) A novel intronic mutation in the DDP1 gene in a family with X-linked dystonia-deafness syndrome. Arch Neurol 62:306–308PubMedCrossRefGoogle Scholar
  70. 70.
    Roesch K, Curran SP, Tranebjaerg L, Koehler CM (2002) Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum Mol Genet 11:477–486PubMedCrossRefGoogle Scholar
  71. 71.
    Roesch K, Hynds PJ, Varga R, Tranebjaerg L, Koehler CM (2004) The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex. Hum Mol Genet 13:2101–2111PubMedCrossRefGoogle Scholar
  72. 72.
    Engl G, Florian S, Tranebjærg L, Mayer TU, Rapaport D (2012) Alterations in expression levels of deafness dystonia protein 1 affect mitochondrial morphology. Hum Mol Genet 21(2):287–299PubMedCrossRefGoogle Scholar
  73. 73.
    Rohrer J, Minegishi Y, Richter D, Eguiguren J, Conley ME (1999) Unusual mutations in Btk: an insertion, a duplication, an inversion, and four large deletions. Clin Immunol 90(1):28–37PubMedCrossRefGoogle Scholar
  74. 74.
    Kim HT, Edwards MJ, Tyson J, Quinn NP, Bitner-Glindzicz M, Bhatia KP (2007) Blepharospasm and limb dystonia caused by Mohr-Tranebjaerg syndrome with a novel splice-site mutation in the deafness/dystonia peptide gene. Mov Disord 22:1328–1331PubMedCrossRefGoogle Scholar
  75. 75.
    Jyonouchi H, Geng L, Toruner GA, Vinekar K, Feng D, Fitzgerald-Bocarsly P (2007) Monozygous twins with a microdeletion syndrome involving BTK, DDP1, and two other genes; evidence of intact dendritic cell development and TLR responses. Eur J Pediatr 167:317–321PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Department of AudiologyBispebjerg HospitalCopenhagenDenmark
  2. 2.Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine (ICMM)The Panum Institute, University of CopenhagenCopenhagenDenmark

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