Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X linked recessive deafness accounts for only 1.7% of all childhood deafness. Only a few of the at least 28 different X linked syndromes associated with hearing impairment have been characterised at the molecular level. In 1960, a large Norwegian family was reported with early onset progressive sensorineural deafness, which was indexed in McKusick as DFN-1, McKusick 304700. No associated symptoms were described at that time. This family has been restudied clinically. Extensive neurological, neurophysiological, neuroradiological, and biochemical, as well as molecular techniques, have been applied to characterise the X linked recessive syndrome. The family history and extensive characterisation of 16 affected males in five generations confirmed the X linked recessive inheritance and the postlingual progressive nature of the sensorineural deafness. Some obligate carrier females showed signs of minor neuropathy and mild hearing impairment. Restudy of the original DFN-1 family showed that the deafness is part of a progressive X linked recessive syndrome, which includes visual disability leading to cortical blindness, dystonia, fractures, and mental deficiency. Linkage analysis indicated that the gene was linked to locus DXS101 in Xq22 with a lod score of 5.37 (zero recombination). Based on lod-1 support interval of the multipoint analysis, the gene is located in a region spanning from 5 cM proximal to 3 cM distal to this locus. As the proteolipid protein gene (PLP) is within this region and mutations have been shown to be associated with non-classical PMD (Pelizaeus-Merzbacher disease), such as complex X linked hereditary spastic paraplegia, PLP may represent a candidate gene for this disorder. This family represents a new syndrome (Mohr-Tranebjaerg syndrome, MTS) and provides significant new information about a new X linked recessive sydromic type of deafness which was previously thought to be isolated deafness.
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PMID:A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. 764 52

A new X-linked recessive deafness syndrome was recently reported and mapped to Xq22 (Mohr-Tranebjaerg syndrome). In addition to deafness, the patients had visual impairment, dystonia, fractures, and mental deterioration. The female carriers did not have any significant manifestations of the syndrome. We examined X chromosome inactivation in 8 obligate and 12 possible carriers by using a polymerase chain reaction analysis of the methylation-dependent amplification of the polymorphic triplet repeat at the androgen receptor locus. Seven of 8 obligate carriers and 1 of 5 carriers by linkage analysis had an extremely skewed pattern in blood DNA not found in 30 normal females. The X inactivation pattern in fibroblast DNA from 2 of the carriers with the extremely skewed pattern was also skewed but to a lesser degree than in blood DNA. One obligate carrier had a random X inactivation pattern in both blood and fibroblast DNA. A selection mechanism for the skewed pattern is therefore not likely. The extremely skewed X inactivation in 8 females of 3 generations in this family may be caused by a single gene that influences skewing of X chromosome inactivation.
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PMID:Inheritance of skewed X chromosome inactivation in a large family with an X-linked recessive deafness syndrome. 882 45

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. More recently, it was shown that this original DFN-1 family represented a new type of recessive neurodegenerative syndrome characterized by postlingual progressive sensorineural deafness as the first presenting symptom in early childhood, followed by progressive dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. This new disorder, termed Mohr-Tranebjaerg syndrome (referred to here as DFN-1/MTS) was mapped to the Xq21.3-Xq22 region2. Using positional information from a patient with a 21-kb deletion in chromosome Xq22 and sensorineural deafness along with dystonia, we characterized a novel transcript lying within the deletion as a candidate for this complex syndrome. 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. This gene, named DDP (deafness/ dystonia peptide), shows high levels of expression in fetal and adult brain. The DDP protein demonstrates striking similarity to a predicted Schizosaccharomyces pombe protein of no known function. Thus, is it likely that the DDP gene encodes an evolutionarily conserved novel polypeptide necessary for normal human neurological development.
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PMID:A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. 884 Nov 89

The human deafness dystonia syndrome results from the mutation of a protein (DDP) of unknown function. We show now that DDP is a mitochondrial protein and similar to five small proteins (Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p) of the yeast mitochondrial intermembrane space. Tim9p, Tim10p, and Tim12p mediate the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane and interact structurally and functionally with Tim8p and Tim13p. DDP is most similar to Tim8p. Tim8p exists as a soluble 70-kDa complex with Tim13p and Tim9p, and deletion of Tim8p is synthetically lethal with a conditional mutation in Tim10p. The deafness dystonia syndrome thus is a novel type of mitochondrial disease that probably is caused by a defective mitochondrial protein-import system.
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PMID:Human deafness dystonia syndrome is a mitochondrial disease. 1005 50

The Mohr-Tranebjaerg syndrome (MTS), a neurodegenerative syndrome characterized by progressive sensorineural hearing loss, dystonia, mental retardation and blindness, is a mitochondrial disease caused by mutations in the deafness/dystonia peptide 1 (DDP1) gene. DDP1 shows similarity to the yeast proteins Tim9, Tim10 and Tim12, components of the mitochondrial import machinery for carrier proteins. Here, we show that DDP1 belongs to a large family of evolutionarily conserved proteins. We report the identification, chromosomal localization and expressional analysis of six human family members which represent further candidate genes for neurodegenerative diseases.
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PMID:The mitochondrial TIM22 preprotein translocase is highly conserved throughout the eukaryotic kingdom. 1061 80

Primary dystonias are movement disorders with dystonia as a major symptom. They are frequently inherited as Mendelian traits. There are at least eight clinically distinct autosomal dominant and two X-linked recessive forms. In addition, pedigree analyses suggest the occurrence of an autosomal recessive variant. The clinical classification is increasingly being replaced by a genetic one. To date gene loci have been identified in at least six autosomal dominant forms, i.e., in idiopathic torsion dystonia (9q34), focal dystonia (18p), adult-onset idiopathic torsion dystonia of mixed type (8p21-q22), dopa-responsive dystonia (14q22.1-q22.2), and paroxysmal dystonic choreoathetosis (2q25-q33; 1p21-p13.3). Gene loci in the X-linked recessive forms have been assigned to Xq13.1 in the X-linked dystonia parkinsonism syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental retardation. The disease genes have been identified in two autosomal dominant forms and in one X-linked recessive form. Mutations in a gene coding for an ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the GTP cyclohydrolase 1 gene is mutated in dopa-responsive dystonia (DYT5). In sensorineural deafness, dystonia, and mental retardation, mutations were found in the gene DDP coding for a polypeptide of unknown function. This article reviews the clinical and molecular genetics of primary dystonias, critically discusses present findings, and proposes referring to the known forms, most of which can be distinguished by genetic criteria, as dystonias 1-12.
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PMID:Clinical and molecular genetics of primary dystonias. 1073 19

We report the first de novo mutation in the DDP gene in a Dutch 11-year-old boy with deafness and dystonia. 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. The clinical presentation was uniformly characterised by sensorineural hearing loss, dystonia, mental deterioration, paranoid psychotic features, and optic atrophy, indicating progressive neurodegeneration. Our report illustrates that de novo mutations occur and that a missense mutation, C66W, may cause an equally severe clinical picture. 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. The association of deafness-dystonia syndrome with a missense mutation provides valuable information for in vitro investigations of the functional properties of the deafness-dystonia peptide which was recently shown to be the human homolog of a yeast protein, Tim8p, belonging to a family of small Tim proteins involved in intermembrane protein transport in mitochondria.
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PMID:A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome. 1087 69

Hearing loss in patients with X-linked agammaglobulinemia is often attributed to recurrent infections. However, recent genetic studies suggest a different etiology in some patients. We present three unrelated patients, 6, 9, and 14 years of age, with large deletions of the terminal portion of the Bruton tyrosine kinase (Btk) gene extending 4.2-19 kb beyond the 3' end of the gene. The DNA immediately downstream of the 3' end of Btk contains the deafness-dystonia protein gene (DDP). Mutations in this gene have recently been shown to underlie the Mohr-Tranebjaerg syndrome, which is characterized by sensorineural deafness, dystonia, and mental deficiency. Besides the immunodeficiency, our patients exhibited progressive sensorineural deafness. The clue to an associated hearing problem was delayed development of speech in one patient and post-lingual deafness noticed between the age of 3-4 years in the other two. These patients have not yet exhibited significant associated neurologic deficits.
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PMID:A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. 1133 84

Paraganglioma (PGL) is a rare disorder characterized by tumors of the head and neck region. Between 10% and 50% of cases of PGL are familial, and the disease is autosomal dominant and subject to age-dependent penetrance and imprinting. The paraganglioma gene (PGL1) has been mapped to 11q22.3-q23, and recently germline mutations in the SDHD gene have been identified. The SDHD region contains another gene, DPP2/TIMM8B, the homolog of which causes dystonia and deafness seen in Mohr-Tranebjaerg syndrome. Using four PGL pedigrees, two of which exhibit coinheritance of PGL and sensorineural hearing loss or tinnitus, analysis of 14 microsatellite markers provided support for linkage to the PGL1 locus. Sequence analysis identified novel mutations in exon 1 and exon 3 of the SDHD gene, including a novel two base pair deletion in exon 3 creating a premature stop codon at position 67; a novel three base pair deletion in exon 3 resulting in the loss of Tyr-93; a missense mutation in exon 3 resulting in the substitution of Leu-81 for Pro-81; and a novel G-to-C substitution in exon 1 resulting in the substitution of Met-1 for Ile-1. No base changes were detected in the DPP2/TIMM8B gene. There was no apparent loss of heterozygosity at the site of the SDHD mutations. However, RT-PCR analysis of tumor samples showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. This has not previously been shown for this disorder. The inheritance and expression of the SDHD gene is consistent with the PGL1 gene being subject to genomic imprinting.
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PMID:Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. 1139 96

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 DDP1.hTim13 complex is in direct contact with translocation intermediates of human Tim23 in mammalian mitochondria. The human DDP1.hTim13 complex complements the function of the TIM8.13 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.
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PMID:Role of the deafness dystonia peptide 1 (DDP1) in import of human Tim23 into the inner membrane of mitochondria. 1148 96


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