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1.
J Cell Mol Med ; 28(16): e70039, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39180521

RESUMO

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of autosomal dominant movement disorders. Among the SCAs associated with impaired ion channel function, SCA19/22 is caused by pathogenic variants in KCND3, which encodes the voltage-gated potassium channel Kv4.3. SCA19/22 is clinically characterized by ataxia, dysarthria and oculomotor dysfunction in combination with other signs and symptoms, including mild cognitive impairment, peripheral neuropathy and pyramidal signs. The known KCND3 pathogenic variants are localized either in the transmembrane segments, the connecting loops, or the C-terminal region of Kv4.3. We have identified a novel pathogenic variant, c.455A>G (p.D152G), localized in the N-terminus of Kv4.3. It is located in the immediate neighbourhood of the T1 domain, which is responsible for multimerization with the ß-subunit KChIP2b and thus for the formation of functional heterooctamers. Electrophysiological studies showed that p.D152G does not affect channel gating, but reduces the ionic current in Kv4.3, even though the variant is not located in the transmembrane domains. Impaired channel trafficking to the plasma membrane may contribute to this effect. In a patient with a clinical picture corresponding to SCA19/22, p.D152G is the first pathogenic variant in the N-terminus of Kv4.3 to be described to date with an effect on ion channel activity.


Assuntos
Canais de Potássio Shal , Ataxias Espinocerebelares , Humanos , Canais de Potássio Shal/genética , Canais de Potássio Shal/metabolismo , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia , Masculino , Feminino , Animais , Ativação do Canal Iônico , Células HEK293 , Proteínas Interatuantes com Canais de Kv/metabolismo , Proteínas Interatuantes com Canais de Kv/genética , Pessoa de Meia-Idade , Mutação/genética , Degenerações Espinocerebelares
2.
J Med Genet ; 56(8): 499-511, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30910913

RESUMO

BACKGROUND: Spinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date. METHODS: We derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2+/- HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2-/- murine fibroblasts. RESULTS: We found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells. CONCLUSION: Our data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2+/- cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants.


Assuntos
Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Variação Genética , Haploinsuficiência , Metaloendopeptidases/genética , Domínios Proteicos/genética , Estresse Fisiológico/genética , Proteases Dependentes de ATP/química , Proteases Dependentes de ATP/metabolismo , ATPases Associadas a Diversas Atividades Celulares/química , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Animais , Cálcio/metabolismo , Fibroblastos/metabolismo , Células HEK293 , Humanos , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Biológicos , Ligação Proteica , Multimerização Proteica , Proteólise , Proteostase/genética , Ativação Transcricional
3.
Hum Mol Genet ; 22(5): 941-51, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23184149

RESUMO

X-chromosomal dystonia parkinsonism syndrome (XDP, 'lubag') is associated with sequence changes within the TAF1/DYT3 multiple transcript system. Although most sequence changes are intronic, one, disease-specific single-nucleotide change 3 (DSC3), is located within an exon (d4). Transcribed exon d4 occurs as part of multiple splice variants. These variants include exons d3 and d4 spliced to exons of TAF1, and an independent transcript composed of exons d2-d4. Location of DSC3 in exon d4 and utilization of this exon in multiple splice variants suggest an important role of DSC3 in the XDP pathogenesis. To test this hypothesis, we transfected neuroblastoma cells with four expression constructs, including exons d2-d4 [d2-d4/wild-type (wt) and d2-d4/DSC3] and d3-d4 (d3-d4/wt and d3-d4/DSC3). Expression profiling revealed a dramatic effect of DSC3 on overall gene expression. Three hundred and sixty-two genes differed between cells containing d2-d4/wt and d2-d4/DSC3. Annotation clustering revealed enrichment of genes related to vesicular transport, dopamine metabolism, synapse function, Ca(2+) metabolism and oxidative stress. Two hundred and eleven genes were differentially expressed in d3-d4/wt versus d3-d4/DSC3. Annotation clustering highlighted genes in signal transduction and cell-cell interaction. The data show an important role of physiologically occurring transcript d2-d4 in normal brain function. Interference with this role by DSC3 is a likely pathological mechanism in XDP. Disturbance of dopamine function and of Ca(2+) metabolism can explain abnormal movement; loss of protection against reactive oxygen species may account for the neurodegenerative changes in XDP. Although d3-d4 also affect genes potentially related to neurodegenerative processes, their physiologic role as splice variants of TAF1 awaits further exploration.


Assuntos
Desmocolinas/genética , Dopamina/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Histona Acetiltransferases/genética , Transtornos Parkinsonianos/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Processamento Alternativo , Cálcio/metabolismo , Linhagem Celular , Desmocolinas/metabolismo , Dopamina/metabolismo , Distonia/genética , Distonia/fisiopatologia , Éxons , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Histona Acetiltransferases/metabolismo , Humanos , Íntrons , Neuroblastoma/genética , Neuroblastoma/psicologia , Transtornos Parkinsonianos/fisiopatologia , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
4.
Nat Genet ; 38(4): 447-51, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16501573

RESUMO

Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3(R420H) and KCNC3(F448L) are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases.


Assuntos
Ataxia Cerebelar/genética , Ativação do Canal Iônico , Mutação de Sentido Incorreto , Mutação , Canais de Potássio Shaw/genética , Sequência de Aminoácidos , Animais , Humanos , Dados de Sequência Molecular , Fenótipo , Canais de Potássio Shaw/química , Xenopus laevis
5.
Front Mol Neurosci ; 15: 878236, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493319

RESUMO

Heterozygous pathogenic variants in the STIP1 homologous and U-box containing protein 1 (STUB1) gene have been identified as causes of autosomal dominant inherited spinocerebellar ataxia type 48 (SCA48). SCA48 is characterized by an ataxic movement disorder that is often, but not always, accompanied by a cognitive affective syndrome. We report a severe early onset dementia syndrome that mimics frontotemporal dementia and is caused by the intronic splice donor variant c.524+1G>A in STUB1. Impaired splicing was demonstrated by RNA analysis and in minigene assays of mutated and wild-type constructs of STUB1. The most striking consequence of this splicing impairment was retention of intron 3 in STUB1, which led to an in-frame insertion of 63 amino acids (aa) (p.Arg175_Glu176ins63) into the highly conserved coiled-coil domain of its encoded protein, C-terminus of HSP70-interacting protein (CHIP). To a lesser extent, activation of two cryptic splice sites in intron 3 was observed. The almost exclusively used one, c.524+86, was not predicted by in silico programs. Variant c.524+86 caused a frameshift (p.Arg175fs*93) that resulted in a truncated protein and presumably impairs the C-terminal U-box of CHIP, which normally functions as an E3 ubiquitin ligase. The cryptic splice site c.524+99 was rarely used and led to an in-frame insertion of 33 aa (p.Arg175_Glu176ins33) that resulted in disruption of the coiled-coil domain, as has been previously postulated for complete intron 3 retention. We additionally detected repeat expansions in the range of reduced penetrance in the TATA box-binding protein (TBP) gene by excluding other genes associated with dementia syndromes. The repeat expansion was heterozygous in one patient but compound heterozygous in the more severely affected patient. Therefore, we concluded that the observed severe dementia syndrome has a digenic background, making STUB1 and TBP important candidate genes responsible for early onset dementia syndromes.

6.
J Neurol ; 268(12): 4866-4873, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34037856

RESUMO

Adult-onset ataxias are a genetically and clinically heterogeneous group of movement disorders. In addition to nuclear gene mutations, sequence changes have also been described in the mitochondrial genome. Here, we present findings of mutation analysis of the mitochondrial gene MT-ATP6. We analyzed 94 patients with adult-onset spinocerebellar ataxia (SCA), including 34 sporadic cases. In all patients, common sequence changes found in SCAs such as repeat expansions and point mutations had been excluded previously. We found pathogenic MT-ATP variants in five of these patients (5.32%), two of whom were sporadic. Four of the five mutations have not previously been described in ataxias. All but one of these mutations affect transmembrane helices of subunit-α of ATP synthase. Two mutations (p.G16S, and p.P18S) disrupt transmembrane helix 1 (TMH1), one mutation (p.G167D) affects TMH5, and another one (p.L217P) TMH6. The fifth mutation (p.T96A) describes an amino acid change in close proximity to transmembrane helix 3 (TMH3). The level of heteroplasmy was either complete or very high ranging from 87 to 99%. The high prevalence of pathogenic MT-ATP6 variants suggests that analysis of this gene should be included in the routine workup of both hereditary and sporadic ataxias.


Assuntos
ATPases Mitocondriais Próton-Translocadoras , Ataxias Espinocerebelares , Adulto , Ataxia , Análise Mutacional de DNA , Humanos , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação/genética , Ataxias Espinocerebelares/genética
7.
Arch Neurol ; 61(12): 1956-9, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15596620

RESUMO

BACKGROUND: X-linked dystonia-parkinsonism (XDP) or "lubag" is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. Genetic confirmation is performed through haplotyping or detection of disease-specific changes in the DYT3 gene. OBJECTIVE: To describe the phenotypes and molecular data of 8 symptomatic female patients with XDP from 5 kindreds. METHODS: Case series. RESULTS: The average age of onset of symptoms was 52 years (range, 26-75 years). Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and focal dystonia (cervical) in 1. Seven of 8 patients had slow or no progression of their symptoms and required no treatment. The patient with disabling parkinsonism was responsive to carbidopa/levodopa. Seven were heterozygous for the XDP haplotype, whereas 1 was homozygous. CONCLUSIONS: The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.


Assuntos
Distonia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos Parkinsonianos/genética , Fenótipo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade
8.
J Alzheimers Dis ; 42(1): 109-13, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24844686

RESUMO

Mutations in the gene PSEN2 are a rare cause of early onset Alzheimer's disease (EOAD). PSEN2 sequence variants are often only found in one patient and pathogenicity cannot be formally documented. Here we describe a previously unrecognized sequence change (c.376G>A) in PSEN2 in an EOAD patient and her likewise affected mother. This change results in the exchange of amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). Pathogenicity of the mutation is shown by segregation with disease, evolutionary conservation of E126, and in silico analysis of the mutation.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Mutação de Sentido Incorreto , Presenilina-2/genética , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Análise Mutacional de DNA , Família , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Homologia de Sequência de Aminoácidos
9.
J Mol Neurosci ; 52(4): 493-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24293060

RESUMO

SCA28 is caused by mutations in the AFG3L2 gene. This gene encodes a subunit of the mitochondrial metalloprotease AFG3L2 (AFG3-like protein 2). Clinical features of SCA28 include slow to moderate progressive ataxia, dysarthria, and additional symptoms such as nystagmus, slow saccades, and increased deep tendon reflexes. Here, we report on a novel AFG3L2 mutation in a patient with slowly progressive ataxia and a positive family history. The nucleotide change results in the substitution of an evolutionarily highly conserved tyrosine by histidine (p.Y689H) in the M41 peptidase domain of AFG3L2.


Assuntos
Proteases Dependentes de ATP/genética , Mutação de Sentido Incorreto , Ataxias Espinocerebelares/genética , ATPases Associadas a Diversas Atividades Celulares , Idade de Início , Sequência de Aminoácidos , Substituição de Aminoácidos , Progressão da Doença , Saúde da Família , Feminino , Genes Mitocondriais/genética , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Fenótipo
10.
Arch Neurol ; 67(5): 631-3, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20457965

RESUMO

OBJECTIVE: To connect a new family with early-onset Alzheimer disease (EOAD) in Germany to the American Volga German pedigrees. DESIGN: Pedigree molecular genetic analysis. SETTING: University Medical Centers in Fulda and Giessen, Germany, and in Seattle, Washington. RESULTS: The families from Fulda, Germany, and the American Volga German families with EOAD share the same N141I PSEN2 mutation on an identical haplotypic background. This establishes that the N141I mutation occurred prior to emigration of the families from the Hesse region to Russia in the 1760s, and documents that relatives of the original immigrant families are presently living in Germany with the mutation and the disease. CONCLUSION: A family with the N141I mutation in PSEN2 that presently lives in Germany has been connected to the haplotype that carries the same mutation in pedigrees descended from the Volga Germans. This raises the possibility that the original patient with Alzheimer disease (Auguste D.), who had EOAD and lived in this same region of Germany, may also have had the PSEN2 N141I mutation.


Assuntos
Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Mutação/genética , Presenilina-2/genética , Idade de Início , Doença de Alzheimer/metabolismo , Análise Mutacional de DNA , Feminino , Efeito Fundador , Frequência do Gene/genética , Marcadores Genéticos/genética , Testes Genéticos , Alemanha , Haplótipos , Humanos , Padrões de Herança , Pessoa de Meia-Idade , Linhagem , Federação Russa , Estados Unidos
11.
Mamm Genome ; 18(11): 787-95, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17952504

RESUMO

We analyzed TAF1/DYT3, a complex transcript system that is composed of at least 43 exons. Thirty-eight exons code for TATA box binding protein associated factor I (TAF1). Five downstream exons (d1-d5) of yet unknown function can either form transcripts with TAF1 exons or be transcribed independently. Splice variants can include d (notably d3 and d4) plus at least 12 TAF1 exons (exons 26-37 but not exon 38). These splice variants are highly polymorphic and include alternative exons (e.g., exons 30b, 31b, 32', 34', 35'). The frequency of these splice variants differs greatly in human fetal brain. Data were obtained by both RT-PCR and construction of a plasmid cDNA library. Promoter assays performed in NT2/D1 and in U87 cells demonstrate that TAF1-independent transcription of exons d2-d4 is driven by a TATA box-less promoter that is regulated by transcription factor Ikaros. Antisense transcription of exon d4 is under the control of a LTR promoter. While the 38 exons encoding TAF1 have been highly conserved in eukaryotes, the downstream exons d1-d5 were added to the transcript system much later during evolution and first appear in primates. The study demonstrates the structural and functional evolution of a complex transcript system.


Assuntos
Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Processamento Alternativo , Animais , Sequência de Bases , Encéfalo/metabolismo , Linhagem Celular , Primers do DNA/genética , DNA Complementar/genética , Evolução Molecular , Éxons , Feto/metabolismo , Biblioteca Gênica , Histona Acetiltransferases , Humanos , Dados de Sequência Molecular , Primatas/genética , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TATA Box , Sequências Repetidas Terminais , Transcrição Gênica , Transfecção
12.
Mov Disord ; 22(2): 265-7, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17149711

RESUMO

We describe a novel mutation in the gene coding for protein kinase C gamma (PRKCG) in patients of a German family affected with slowly progressive gait ataxia, dysarthria, and nystagmus. The G/T missense mutation occurred in exon 2 of PRKCG and results in a substitution of glycine by valine (G63V) in the evolutionarily highly conserved cysteine-rich region 1/C1 domain of PRKCG. Among the 20 mutations described to date, this is the first mutation located in exon 2 of PRKCG.


Assuntos
Éxons/genética , Mutação Puntual/genética , Proteína Quinase C/genética , Ataxias Espinocerebelares/classificação , Ataxias Espinocerebelares/genética , Análise Mutacional de DNA , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Doenças Raras , Transdução de Sinais
13.
Mov Disord ; 22(12): 1790-3, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17579361

RESUMO

"Lubag" or X-linked dystonia-parkinsonism (XDP) is a genetic syndrome afflicting Filipino men. Intracranial surgical procedures for Lubag have been unsuccessful. We report a 45-year-old Filipino male with genetically confirmed XDP who underwent bilateral pallidal deep brain stimulation (DBS) surgery. The patient started to exhibit improvement on initial programming, most notably of his severe jaw-opening dystonia. At 1-year follow-up, his Burke-Fahn-Marsden dystonia score and motor Unified Parkinson's Disease Rating Scale score were improved by 71% and 62%, respectively, with the stimulators on compared to stimulators off state. Bilateral pallidal DBS may be a viable option for Lubag patients with medically refractory symptoms.


Assuntos
Terapia por Estimulação Elétrica , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Globo Pálido/fisiopatologia , Doença de Parkinson/genética , Doença de Parkinson/terapia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Globo Pálido/efeitos da radiação , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologia
14.
Mov Disord ; 22(5): 732-5, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17265523

RESUMO

This is a single case report of a patient with spinocerebellar ataxia type 2 (SCA2) and severe tremor. Whereas disease progression with prevailing ataxia and dysmetria was slow over the first symptomatic 6 years, 6 months prior to operation were characterized by the development of a severe, debilitating postural tremor rendering the patient unable to independently sit, stand, speak, or swallow. Deep brain stimulation (DBS) at a subthalamic-thalamic electrode position almost completely arrested her tremor. The patient regained the functional state prior to her rapid disease progression allowing a restricted range of daily activities. Her condition has remained approximately stable over the two postoperative years to date. In addition to the efficacy of DBS on cerebellar tremor, the results illustrate a remarkable improvement of the patient's general condition and independence.


Assuntos
Estimulação Encefálica Profunda , Ataxias Espinocerebelares/terapia , Núcleo Subtalâmico/fisiopatologia , Tremor/terapia , Núcleos Ventrais do Tálamo/fisiopatologia , Atividades Cotidianas/classificação , Adulto , Eletrodos Implantados , Feminino , Seguimentos , Humanos , Exame Neurológico , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/fisiopatologia , Torcicolo/diagnóstico , Torcicolo/fisiopatologia , Torcicolo/terapia , Resultado do Tratamento , Tremor/diagnóstico , Tremor/fisiopatologia
15.
Proc Natl Acad Sci U S A ; 100(18): 10347-52, 2003 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-12928496

RESUMO

X-linked dystonia parkinsonism (XDP) is an X-linked recessive adult onset movement disorder characterized by both dystonia and parkinsonism. We report delineation of the disease gene within a 300-kb interval of Xq13.1 by allelic association. Sequencing of this region in a patient revealed five disease-specific single-nucleotide changes (here referred to as DSC) and a 48-bp deletion unique to XDP. One of the DSCs is located within an exon of a not previously described multiple transcript system that is composed of at least 16 exons. There is a minimum of three different transcription start sites that encode four different transcripts. Two of these transcripts include distal portions of the TAF1 gene (TATA-box binding protein-associated factor 1) and are alternatively spliced. Three exons overlap with ING2 (a putative tumor suppressor) and with a homologue of CIS4 (cytokine-inducible SH2 protein 4), both of which are encoded by the opposite strand. Although all DSCs are located within this multiple transcript system, only DSC3 lies within an exon. This exon is used by all alternative transcripts making a pathogenic role of DSC3 in XDP likely. The multiple transcript system is therefore referred to as DYT3 (disease locus in XDP).


Assuntos
Cromossomos Humanos X , Distonia/genética , Ligação Genética , Transtornos Parkinsonianos/genética , Adulto , Sequência de Bases , DNA/química , Feminino , Haplótipos , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas de Saccharomyces cerevisiae/genética
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