Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial DNA (mtDNA) is maternally inherited. After birth, secondary mtDNA defects can arise. MtDNA depletion is a reduction in the amount of mtDNA in particular tissues. Multiple deletions of mtDNA accumulate as somatic mutations in mainly postmitotic tissues. These disorders of mtDNA maintenance frequently show Mendelian inheritance. Positional cloning has identified several genes involved in the control of mtDNA stability. Recessive mutations in the genes ECGF1, dGK, TK2, SUCLA2 and POLG cause mtDNA depletion syndromes (MDS). Generally, MDS has infantile onset tissue specific features. Mutations in the genes ECGF1, ANT1, C10orf2 and POLG are associated with multiple mtDNA deletions. The nature of these mutations is dominant in ANT1, C10orf2 and POLG and recessive in ECGF1, C10orf2 and POLG. Mutations in these genes frequently cause progressive external ophthalmoplegia (PEO). However clinical heterogeneity results in different neurological syndromes with considerable overlap. The most common features are PEO, neuropathy, myopathy, ataxia, epilepsy and hepatopathy.
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PMID:Autosomal disorders of mitochondrial DNA maintenance. 1689 56

Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.
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PMID:Inherited mitochondrial diseases of DNA replication. 1789 33

Cerebellar ataxias with autosomal dominant transmission are rare, but identification of the associated genes has provided insight into the mechanisms that could underlie other forms of genetic or non-genetic ataxias. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes complex multisystemic neurological deficits. The designation of the loci, SCA for spinocerebellar ataxia, indicates the involvement of at least two systems: the spinal cord and the cerebellum. 11 of 18 known genes are caused by repeat expansions in the corresponding proteins, sharing the same mutational mechanism. All other SCAs are caused by either conventional mutations or large rearrangements in genes with different functions, including glutamate signalling (SCA5/SPTBN2) and calcium signalling (SCA15/16/ITPR1), channel function (SCA13/KCNC3, SCA14/PRKCG, SCA27/FGF14), tau regulation (SCA11/TTBK2), and mitochondrial activity (SCA28/AFG3L2) or RNA alteration (SCA31/BEAN-TK2). The diversity of underlying mechanisms that give rise to the dominant cerebellar ataxias need to be taken into account to identify therapeutic targets.
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PMID:Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. 2072 45

Spinocerebellar ataxia type 31 (SCA31) is a relatively common degenerative ataxia in Japan. We recently discovered SCA31 mutation as a complex pentanucleotide repeat containing (TAAAA)(n), (TAGAA)(n), and (TGGAA)(n). The size of this repeat ranged from 2.8 to 3.5 kilo-base pairs (kb). Among these repeats, (TGGAA)(n) repeat appears crucial for SCA31 pathogenesis. The length of this complex repeat inversely correlated with ages of onset in patients. The mutation lies in an intron shared by two different genes, BEAN (brain expressed, associated with NEDD4) and TK2 (thymidine kinase 2), which are transcribed in opposite directions. Thus, the complex pentanucleotide sequence is predicted to be transcribed in both directions, but not necessarily translated into proteins. In situ hybridization analysis in patients' Purkinje cells demonstrated that pentanucleotide repeats transcribed in BEAN direction form RNA aggregates ("RNA foci"). We further found that splicing factors, SFRS1 and SFRS9, binds to (UGGAA)(n), the transcript of (TGGAA)(n) in vitro. These findings may imply that SCA31 conforms to pathogenic mechanisms underlying non-coding repeat disorders, such as myotonic dystrophies (DM1 & DM2), and that SFRS1 and SFRS9 are involved in SCA31 pathogenesis.
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PMID:[Spinocerebellar ataxia type 31]. 2192 37

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase g in concert with accessory proteins such as the mtDNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease.
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PMID:Defects in mitochondrial DNA replication and human disease. 2217 57