Disease relevance of TIMM8A

• Mohr-Tranebjaerg syndrome is a progressive, neurodegenerative disorder caused by loss-of-function mutations in the DDP1/TIMM8A gene [1].
• The human family of Deafness/Dystonia peptide (DDP) related mitochondrial import proteins [2].
• P19 embryonal carcinoma cells transfected with anti sense DDP1 cDNA were frequently dead after subculture and all the survivals expressed endogenous DDP1 mRNA [3].
• Human deafness dystonia syndrome is a mitochondrial disease [4].
• The diagnosis of sensorineural hearing impairment associated with neurologic and visual disability in a male, therefore, should encourage the search for mutations in the DDP gene, even in sporadic cases [5].

Psychiatry related information on TIMM8A

• We now report small deletions in this candidate gene in the original DFN-1/MTS family, and in a family with deafness, dystonia and mental deficiency but not blindness [6].
• Method: Fifty-four parents were assessed for their experiences during hospitalization and by questionnaires regarding grief (MTS), post-traumatic growth, affective symptoms and the visual representation of the baby and the self of the parents (PRISM) [7].
• Cognitive tests included visual information processing, match-to-sample visual search (MTS) and simple and choice reaction times [8].

High impact information on TIMM8A

• This gene, named DDP (deafness/ dystonia peptide), shows high levels of expression in fetal and adult brain [6].
• In 1960, progressive sensorineural deafness (McKusick 304,700, DFN-1) was shown to be X-linked based on a description of a large Norwegian pedigree [6].
• A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness [6].
• Cross-resistance between cisplatin (DDP) and metalloid salts in human cells was sought on the basis that mechanisms that mediate metalloid salt cross-resistance in prokaryotes are evolutionarily conserved [9].
• Two ovarian and two head and neck carcinoma cell lines selected for DDP resistance were found to be cross-resistant to antimony potassium tartrate, which contains trivalent antimony [9].

Chemical compound and disease context of TIMM8A

• A twofold change in the cisplatin (DDP) sensitivity of 2008 human ovarian carcinoma cells is sufficient to reduce tumor response in vivo [10].
• A platinum(II) and 3 platinum(IV) ammine/cycloalkylamine homologous series were evaluated for cytotoxicity and biochemical pharmacology in murine leukemia L1210/0, cis-diamminedichloroplatinum(II)- resistant L1210/DDP, and diaminocyclohexaneplatinum-resistant L1210/1,2-diaminocyclohexane (DACH) cells [11].
• CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity [12].
• The addition of the antifol methotrexate to cisplatin (DDP) produces supraadditive antitumor effects in preclinical studies, but in the clinic this combination of two nephrotoxic drugs is limited by excessive toxicity [13].
• RESULTS: Numerous articles have reported an overall response rate of 47% (95% confidence limit, 39.25 to 54.75) when patients with metastatic melanoma are treated with the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and TAM (DBDT) [14].

Biological context of TIMM8A

• 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 CX(3)C' motif [15].
• In comparison to mouse Bruton's tyrosine kinase (Btk) locus, the coding region spans 2 exons and the splice point is the same as human DDP1 [3].
• Complementary DNA of mouse deafness dystonia peptide 1 (DDP1) was isolated from adipocyte cDNA library and expressed in mammalian cells [3].
• A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome [5].
• Recently, a processed pseudogene of the X-chromosome-linked gene TIMM8A was inserted downstream of GCG [16].

Anatomical context of TIMM8A

• A lymphoblast cell line derived from an MTS patient had decreased NADH levels and defects in mitochondrial protein import [17].
• Thus, insufficient NADH shuttling, linked with changes in Ca2+ concentration, in sensitive cells of the central nervous system might contribute to the pathologic process associated with MTS [17].
• DDP1 tagged with FLAG localized in mitochondria and cytoplasm of COS7 cells [3].
• The Mohr-Tranebjaerg-Jensen deafness-dystonia-optic atrophy protein DDP/TIMM8a is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import [18].
• 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 [19].

Associations of TIMM8A with chemical compounds

• We describe a novel guanine deletion at nucleotide 108 of the DDP gene in a family with Mohr-Tranebjaerg syndrome, which terminates this 97-amino acid protein at codon 25 [20].
• The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein [21].
• The effect of enalapril on EPC mobilization could be substantially blocked by Diprotin-A, a DDP IV antagonist [22].
• DDP coordinates Zn(2+), and Zn(2+) was found to stimulate the DDP-STAM1 interaction in vitro [18].
• Neither bombesin nor TNF alpha changed the accumulation of DDP, glutathione content, or glutathione-S-transferase activity in 2008 cells [10].

Physical interactions of TIMM8A

• Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking [18].

Other interactions of TIMM8A

• Dystonia with and without deafness is caused by TIMM8A mutation [23].
• Previously reported mutations in the DDP gene have all been frameshifts/nonsense mutations or deletion of the entire gene as part of a larger deletion encompassing the BTK gene [5].
• In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization [21].
• Thus, the DDP-STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane [18].

Analytical, diagnostic and therapeutic context of TIMM8A

• Northern blot analysis suggests that mouse DDP1 expresses ubiquitously [3].
• Sequence analysis of the patient's DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon [21].
• We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein "pull downs," and nuclear redistribution assays [18].
• The effects of cyclophosphamide (Cy), doxorubicin (Dx), cisplatin (DDP), melphalan (L-PAM), and vincristine (VCR) on various human and animal tumor lines with different growth rates, growing as xenografts in NMRI (nu/nu) mice, were studied [24].
• Diethyldithiocarbamate (DDTC) has been shown to provide protection against most clinically significant toxic effects from cisplatin (DDP) without inhibiting tumor response in a variety of murine animal models [25].

References