A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness–dystonia–optic atrophy syndrome

Tranebjærg, Lisbeth; Hamel, B.C.J.; Gabreëls, F.J.M.; Renier, W.O.; Ghelue, Marijke Van

doi:10.1038/sj.ejhg.5200483

Cited by 76 publications

(43 citation statements)

References 9 publications

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“…Recently, a first case of Mohr-Tranebjaerg syndrome with a missense mutation in DDP1/TIMM8A was reported (27). The mutated gene encodes a full-length protein; however, the clinical outcome of this patient is indistinguishable from published clinical courses of patients with loss-offunction mutations leading to absent or truncated DDP1 proteins.…”

Section: Discussionmentioning

confidence: 63%

“…This cysteine to tryptophan exchange at amino acid position 66 is currently the only missense mutation known to cause Mohr-Tranebjaerg syndrome (27). We show that the DDP1 C66W is efficiently imported into mitochondria and correctly sorted into the intermembrane space.…”

mentioning

confidence: 88%

“…Yeast-A patient with Mohr-Tranebjaerg syndrome was recently reported to carry a mutation in DDP1 leading to an exchange of cysteine to tryptophan at amino acid position 66 (DDP1 C66W ) (27). To functionally characterize the C66W substitution, we expressed the mutant human DDP1 C66W protein in yeast cells carrying disrupted alleles of TIM8 and TIM13 (⌬8/⌬13) (21).…”

Section: The C66w Exchange Impairs the Function Of Ddp1 Inmentioning

confidence: 99%

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The C66W Mutation in the Deafness Dystonia Peptide 1 (DDP1) Affects the Formation of Functional DDP1·TIM13 Complexes in the Mitochondrial Intermembrane Space

Hofmann¹,

Rothbauer²,

Mühlenbein³

et al. 2002

Journal of Biological Chemistry

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Mohr-Tranebjaerg syndrome is a progressive, neurodegenerative disorder caused by loss-of-function mutations in the DDP1/TIMM8A gene. DDP1 belongs to a family of evolutionary conserved proteins that are organized in hetero-oligomeric complexes in the mitochondrial intermembrane space. They mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane. All of them share a conserved Cys 4 metal binding site proposed to be required for the formation of zinc fingers. So far, the only missense mutation known to cause a full-blown clinical phenotype is a C66W exchange directly affecting this Cys 4 motif. Here, we show that the mutant human protein is efficiently imported into mitochondria and sorted into the intermembrane space. In contrast to wild-type DDP1, it does not complement the function of its yeast homologue Tim8. The C66W mutation impairs binding of Zn 2؉ ions via the Cys 4 motif. As a consequence, the mutated DDP1 is incorrectly folded and loses its ability to assemble into a hetero-hexameric 70-kDa complex with its cognate partner protein human Tim13. Thus, an assembly defect of DDP1 is the molecular basis of Mohr-Tranebjaerg syndrome in patients carrying the C66W mutation.With the exception of a few components of the oxidative phosphorylation machinery, all mitochondrial proteins are encoded by nuclear genes and synthesized on cytosolic ribosomes.

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Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 88%

Section: The C66w Exchange Impairs the Function Of Ddp1 Inmentioning

confidence: 99%

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The C66W Mutation in the Deafness Dystonia Peptide 1 (DDP1) Affects the Formation of Functional DDP1·TIM13 Complexes in the Mitochondrial Intermembrane Space

Hofmann¹,

Rothbauer²,

Mühlenbein³

et al. 2002

Journal of Biological Chemistry

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“…4 Mutations in TIMM8A cause the rare X-linked neurodegenerative Mohr-Tranebjaerg syndrome (MTS), which is clinically characterized by a progressive neurological deficits, including early onset of sensorineural deafness. [5][6][7] A large number of BTK mutations, scattered over the entire gene, have been reported and deposited in an international mutation database (http://bioinf.uta.fi/BTKbase/). The most commonly found mutations are missense (34%), followed by nonsense mutations (20%).…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes

et al. 2011

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Patients with X-linked agammaglobulinemia (XLA) can present with sensorineural deafness. This can result from a gross deletion that not only involved the Bruton's tyrosine kinase (BTK) gene, but also TIMM8A, mutations in which underlie the MohrTranebjaerg syndrome (MTS). We analyzed the genomic break points observed in three XLA-MTS patients and compared these with deletions break points from XLA patients. Patient 1 had a 63-kb deletion with break points in intron 15 of BTK and 4 kb upstream of TAF7L. Patients 2 and 3 had 149.7 and 196 kb deletions comprising BTK, TIMM8A, TAF7L and DRP2. The break points in patients 1 and 3 were located in Alu and endogenous retrovirus (ERV) repeats, whereas the break points in patient 2 did not show involvement of transposable elements. Comparison of gross deletion sizes and involvement of transposable elements in XLA and XLA-MTS patients from the literature showed preferential involvement of Alu elements in smaller deletions (o10 kb). These results show further insights into the molecular mechanisms underlying gross deletions in patients with primary immunodeficiency.

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“…Most of the DDP1 mutations are loss-of-function mutations predicted to lead to an absent or a truncated gene product. So far, only one missense mutation was found causing a cysteine to tryptophan exchange (C66W) within the Cys 4 motif (25).…”

mentioning

confidence: 99%

Role of the Deafness Dystonia Peptide 1 (DDP1) in Import of Human Tim23 into the Inner Membrane of Mitochondria

Rothbauer¹,

Hofmann²,

Mühlenbein³

et al. 2001

Journal of Biological Chemistry

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Tim8 and Tim13 of yeast belong to a family of evolutionary conserved zinc finger proteins that are organized in hetero-oligomeric complexes in the mitochondrial intermembrane space. Mutations in DDP1 (deafness dystonia peptide 1), the human homolog of Tim8, are associated with the Mohr-Tranebjaerg syndrome, a progressive neurodegenerative disorder. We show that DDP1 acts with human Tim13 in a complex in the intermembrane space. The DDP1⅐hTim13 complex is in direct contact with translocation intermediates of human Tim23 in mammalian mitochondria. The human DDP1⅐hTim13 complex complements the function of the TIM8⅐13 complex in yeast and facilitates import of yeast and human Tim23. Thus, the pathomechanism underlying the Mohr-Tranebjaerg syndrome may involve an impaired biogenesis of the human TIM23 complex causing severe pleiotropic mitochondrial dysfunction.The vast majority of mitochondrial proteins are encoded as precursors in the nuclear genome. Mitochondrial biogenesis is, therefore, dependent on the import and sorting of the nuclear encoded precursor proteins into mitochondrial subcompartments. In eukaryotes three distinct preprotein import systems located in the mitochondrial outer and inner membrane have been described (1-5). The outer membrane contains a general preprotein translocase, the TOM 1 complex, which mediates the recognition and binding of preproteins and their transfer across the outer membrane. This complex is most likely used by all nuclear encoded precursors. Import into and across the inner membrane is mediated by two distinct inner membrane translocases, the TIM22 and the TIM23 complexes. Both TIM complexes cooperate with the TOM complex but differ in their substrate specificity (6 -11). The TIM23 complex mediates import of preproteins with a positively charged matrix targeting signal into the mitochondrial matrix space and into the inner membrane (6, 12, 13). The translocation of such precursors into the matrix requires the membrane potential ⌬ across the inner membrane and ATP in the matrix. The ⌬ drives the translocation of the presequences through the protein-conducting channel of the TIM23 complex which is formed by the membrane-integrated proteins Tim23 and Tim17 (6,12). A molecular motor that is attached to the inner side of this channel then promotes further translocation of the mature portion of the preproteins into the matrix. This motor consists of the peripheral membrane protein Tim44, the mitochondrial Hsp70, and the nucleotide exchange factor Mge1. Together, these components in repeated ATP-dependent reaction cycles facilitate the vectorial translocation into the matrix in a stepwise manner (14).The TIM22 complex mediates the insertion of a class of hydrophobic proteins with internal targeting signals into the inner membrane (7)(8)(9)(10)(11)(15)(16)(17). Typical substrates are members of the mitochondrial carrier family and other integral inner membrane proteins that are synthesized without a matrix-targeting signal. Insertion of these precursors into the inner membrane is s...

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A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness–dystonia–optic atrophy syndrome

Cited by 76 publications

References 9 publications

The C66W Mutation in the Deafness Dystonia Peptide 1 (DDP1) Affects the Formation of Functional DDP1·TIM13 Complexes in the Mitochondrial Intermembrane Space

The C66W Mutation in the Deafness Dystonia Peptide 1 (DDP1) Affects the Formation of Functional DDP1·TIM13 Complexes in the Mitochondrial Intermembrane Space

Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes

Role of the Deafness Dystonia Peptide 1 (DDP1) in Import of Human Tim23 into the Inner Membrane of Mitochondria

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