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Find video protocols related to scientific articles indexed in Pubmed.
EIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts.
J. Med. Genet.
PUBLISHED: 11-05-2014
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Missense mutations in the eukaryotic translation initiation factor 4-? 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with autosomal-dominant segregation showed a heterozygous missense mutation and additional patients were found to have unique sequence variants that have not been observed in controls. Subsequent studies have reported contradictory findings.
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Genome sequencing identifies a novel mutation in ATP1A3 in a family with dystonia in females only.
J. Neurol.
PUBLISHED: 08-10-2014
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Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Several genetic causes of dystonia have been elucidated but genetic causes of dystonia specifically affecting females have not yet been described. In the present study, we investigated a large dystonia family from New Zealand in which only females were affected. They presented with a generalized form of the disorder including laryngeal, cervical, and arm dystonia. We found a novel, likely disease-causing, three base-pair deletion (c.443_445delGAG, p.Ser148del) in ATP1A3 in this family by combining genome and exome sequencing. Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome. Therefore, we re-examined our patients with a specific focus on typical symptoms of these conditions. It turned out that all patients reported a rapid onset of dystonic symptoms following a trigger suggesting a diagnosis of RDP. Notably, none of the patients showed clear symptoms of parkinsonism or symptoms specific for AHC or CAPOS. The ATP1A3 gene is located on chromosome 19q13.2, thus, providing no obvious explanation for the preponderance to affect females. Interestingly, we also identified one unaffected male offspring carrying the p.Ser148del mutation suggesting reduced penetrance of this mutation, a phenomenon that has also been observed for other RDP-causing mutations in ATP1A3. Although phenotypic information in this family was initially incomplete, the identification of the p.Ser148del ATP1A3 mutation elicited clinical re-examination of patients subsequently allowing establishing the correct diagnosis, a phenomenon known as "reverse phenotyping".
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Next generation sequencing and the future of genetic diagnosis.
Neurotherapeutics
PUBLISHED: 07-24-2014
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The introduction of next generation sequencing (NGS) has led to an exponential increase of elucidated genetic causes in both extremely rare diseases and common but heterogeneous disorders. It can be applied to the whole or to selected parts of the genome (genome or exome sequencing, gene panels). NGS is not only useful in large extended families with linkage information, but may also be applied to detect de novo mutations or mosaicism in sporadic patients without a prior hypothesis about the mutated gene. Currently, NGS is applied in both research and clinical settings, and there is a rapid transition of research findings to diagnostic applications. These developments may greatly help to minimize the "diagnostic odyssey" for patients as whole-genome analysis can be performed in a few days at reasonable costs compared with gene-by-gene analysis based on Sanger sequencing following diverse clinical tests. Despite the enthusiasm about NGS, one has to keep in mind its limitations, such as a coverage and accuracy of?
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THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression.
Biochim. Biophys. Acta
PUBLISHED: 05-11-2014
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THAP1 encodes a transcription factor but its regulation is largely elusive. TOR1A was shown to be repressed by THAP1 in vitro. Notably, mutations in both of these genes lead to dystonia (DYT6 or DYT1). Surprisingly, expressional changes of TOR1A in THAP1 mutation carriers have not been detected indicating additional levels of regulation. Here, we investigated whether THAP1 is able to autoregulate its own expression. Using in-silico prediction, luciferase reporter gene assays, and (quantitative) chromatin immunoprecipitation (ChIP), we defined the THAP1 minimal promoter to a 480bp-fragment and demonstrated specific binding of THAP1 to this region which resulted in repression of the THAP1 promoter. This autoregulation was disturbed by different DYT6-causing mutations. Two mutants (Ser6Phe, Arg13His) were shown to be less stable than wildtype THAP1 adding to the effect of reduced binding to the THAP1 promoter. Overexpressed THAP1 is preferably degraded through the proteasome. Notably, endogenous THAP1 expression was significantly reduced in cells overexpressing wildtype THAP1 as demonstrated by quantitative PCR. In contrast, higher THAP1 levels were detected in induced pluripotent stem cell (iPS)-derived neurons from THAP1 mutation carriers. Thus, we identified a feedback-loop in the regulation of THAP1 expression and demonstrated that mutant THAP1 leads to higher THAP1 expression levels. This compensatory autoregulation may contribute to the mean age at onset in the late teen years or even reduced penetrance in some THAP1 mutation carriers.
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Mutations in GNAL: a novel cause of craniocervical dystonia.
JAMA Neurol
PUBLISHED: 02-19-2014
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Mutations in the GNAL gene have recently been shown to cause primary torsion dystonia. The GNAL-encoded protein (G?olf) is important for dopamine D1 receptor function and odorant signal transduction. We sequenced all 12 exons of GNAL in 461 patients from Germany, Serbia, and Japan, including 318 patients with dystonia (190 with cervical dystonia), 51 with hyposmia and Parkinson disease, and 92 with tardive dyskinesia or acute dystonic reactions.
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Unraveling cellular phenotypes of novel TorsinA/TOR1A mutations.
Hum. Mutat.
PUBLISHED: 02-14-2014
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A three-nucleotide (GAG) deletion (?E) in TorsinA (TOR1A) has been identified as the most common cause of dominantly inherited early-onset torsion dystonia (DYT1). TOR1A encodes a chaperone-like AAA+-protein localized in the endoplasmic reticulum. Currently, only three additional, likely mutations have been reported in single dystonia patients. Here, we report two new, putative TOR1A mutations (p.A14_P15del and p.E121K) that we examined functionally in comparison with wild-type (WT) protein and two known mutations (?E and p.R288Q). While inclusion formation is a characteristic feature for ?E TOR1A, elevated levels of aggregates for other mutations were not observed when compared with WT TOR1A. WT and mutant TOR1A showed preferred degradation through the autophagy-lysosome pathway, which is most pronounced for p.A14_P15del, p.R288Q, and ?E TOR1A. Notably, blocking of the autophagy pathway with bafilomycin resulted in a significant increase in inclusion formation in p.E121K TOR1A. In addition, all variants had an influence on protein stability. Although the p.A14_P15del mutation affects the proposed oligomerization domain of TOR1A, this mutation did not disturb the ability to dimerize. Our findings demonstrate functional changes for all four mutations on different levels. Thus, both diagnostic and research genetic screening of dystonia patients should not be limited to testing for the ?E mutation.
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Mutations in VPS26A are not a frequent cause of Parkinson's disease.
Neurobiol. Aging
PUBLISHED: 01-15-2014
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VPS35 mutations have been identified as a cause of autosomal dominantly inherited Parkinson's disease (PD). VPS35 interacts with VPS26A in the retromer complex that links mitochondrial and lysosomal pathways, which have both been shown to be dysfunctional in PD. Thus, mutations in VPS26A may be associated with PD. To test this hypothesis, we screened 245 idiopathic PD patients and 185 control subjects for mutations in the retromer subunit VPS26A. We found 2 novel missense variants in patients and 2 known missense variants in control subjects. The missense variants were unlikely to be disease causing, suggesting that VPS26A mutations are not a frequent cause of PD.
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De novo mutation in the GNAL gene causing seemingly sporadic dystonia in a Serbian patient.
Mov. Disord.
PUBLISHED: 01-13-2014
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Mutations in GNAL (DYT25) have recently been established as the first confirmed cause of focal or segmental adult-onset dystonia. Mutation carriers show craniocervical involvement; however, the GNAL mutational and phenotypic spectrum remain to be further characterized, and guidelines for diagnostic testing need to be established.
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Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.
Epilepsia
PUBLISHED: 01-06-2014
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Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the ?II -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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Genome-wide association study in musicians dystonia: A risk variant at the arylsulfatase G locus?
Mov. Disord.
PUBLISHED: 09-16-2013
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Musicians dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writers dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P?
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Recessive dystonia-ataxia syndrome in a Turkish family caused by a COX20 (FAM36A) mutation.
J. Neurol.
PUBLISHED: 07-18-2013
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DYTCA is a syndrome that is characterized by predominant dystonia and mild cerebellar ataxia. We examined two affected siblings with healthy, consanguineous, Turkish parents. Both patients presented with a combination of childhood-onset cerebellar ataxia, dystonia, and sensory axonal neuropathy. In the brother, dystonic features were most pronounced in the legs, while his sister developed torticollis. Routine diagnostic investigations excluded known genetic causes. Biochemical analyses revealed a mitochondrial respiratory chain complex IV and a coenzyme Q10 deficiency in a muscle biopsy. By exome sequencing, we identified a homozygous missense mutation (c.154A >C; p.Thr52Pro) in both patients in exon 2 of the COX20 (FAM36A) gene, which encodes a complex IV assembly factor. This variant was confirmed by Sanger sequencing, was heterozygous in both parents, and was absent from 427 healthy controls. The exact same mutation was recently reported in a patient with ataxia and muscle hypotonia. Among 128 early-onset dystonia and/or ataxia patients, we did not detect any other patient with a COX20 mutation. cDNA sequencing and semi-quantitative analysis were performed in fibroblasts from one of our homozygous mutation carriers and six controls. In addition to the exchange of an amino acid, the mutation led to a shift in splicing. In conclusion, we extend the phenotypic spectrum of a recently identified mutation in COX20 to a recessively inherited, early-onset dystonia-ataxia syndrome that is characterized by reduced complex IV activity. Further, we confirm a pathogenic role of this mutation in cerebellar ataxia, but this mutation seems to be a rather rare cause.
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Mortalin mutations are not a frequent cause of early-onset Parkinson disease.
Neurobiol. Aging
PUBLISHED: 04-12-2013
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Dysfunctional mitochondria and the mitochondrial chaperone mortalin (HSPA9, GRP75) have been implicated in the pathogenesis of Parkinson disease (PD). We screened 139 early-onset PD (EOPD) patients for mutations in mortalin revealing one missense change (p.L358P) that was absent in 279 control individuals. We also found one additional missense variant among the controls (p.T333K). Although both missense changes were predicted to be disease causing, we detected no differences in subcellular localization, mitochondrial morphology, or respiratory function between wild-type and mutant mortalin. These findings suggest that variants in mortalin (1) are not a major cause of EOPD; (2) occur in patients and controls; and (3) do not lead to functional impairment of mitochondria.
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The protective effect of LRRK2 p.R1398H on risk of Parkinsons disease is independent of MAPT and SNCA variants.
Neurobiol. Aging
PUBLISHED: 04-09-2013
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The best validated susceptibility variants for Parkinsons disease are located in the ?-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ? 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinsons disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
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Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.
Nat. Genet.
PUBLISHED: 04-05-2013
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Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor ? (PDGF-R?) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R?. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
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X-linked Dystonia-Parkinsonism manifesting in a female patient due to atypical turner syndrome.
Mov. Disord.
PUBLISHED: 02-06-2013
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Recessive X-linked dystonia-parkinsonism almost exclusively affects men. We investigated the genetic mechanisms causing this disorder in a female patient.
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Genetics of dystonia: whats known? Whats new? Whats next?
Mov. Disord.
PUBLISHED: 01-02-2013
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Although all forms of dystonia share the core clinical features of involuntary dystonic dyskinesia, there is not only marked phenotypic but also etiologic heterogeneity. Isolated dystonia can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25). Combined dystonias (with parkinsonism or myoclonus) are further subdivided into persistent (TAF1 [DYT3], GCHI [DYT5], SGCE [DYT11], ATP1A3 [DYT12]), PRKRA (DYT16), and paroxysmal (MR-1 [DYT8], PRRT2 [DYT10], SLC2A1 [DYT18]. With the advent of next-generation sequencing, an unprecedented number of new dystonia genes have recently been described, including 4 in the past 12 months. Despite the need for independent confirmation, these recent findings raise 2 important questions regarding (1) the role of genetics in dystonia overall and (2) the role of different molecular mechanisms in dystonia pathogenesis. The genetic contribution to dystonia represents a continuum ranging from genetic susceptibility factors of small effect to causative genes with markedly reduced penetrance to those with full penetrance. Equally diverse and complex are the pathways and neuronal function(s) putatively involved in dystonia pathogenesis including dopamine signaling, intracellular transport, cytoskeletal dynamics, transcriptional regulation, cell-cycle control, ion channel function, energy metabolism, signal transduction, and detoxification mechanisms. In the next decade of dystonia research, we expect to see the discovery of additional dystonia genes and susceptibility factors. In this context, it will be of great interest to explore whether the diverse cellular functions of the known dystonia proteins may be linked to shared pathways and thus complete the complex puzzle of dystonia pathogenesis. © 2013 Movement Disorder Society.
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Identification and functional analysis of novel THAP1 mutations.
Eur. J. Hum. Genet.
PUBLISHED: 08-17-2011
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Mutations in THAP1 have been associated with dystonia 6 (DYT6). THAP1 encodes a transcription factor that represses the expression of DYT1. To further evaluate the mutational spectrum of THAP1 and its associated phenotype, we sequenced THAP1 in 567 patients with focal (n = 461), segmental (n = 68), or generalized dystonia (n = 38). We identified 10 novel variants, including six missense substitutions within the DNA-binding Thanatos-associated protein domain (Arg13His, Lys16Glu, His23Pro, Lys24Glu, Pro26Leu, Ile80Val), a 1bp-deletion downstream of the nuclear localization signal (Asp191Thrfs*9), and three alterations in the untranslated regions. The effect of the missense variants was assessed using prediction tools and luciferase reporter gene assays. This indicated the Ile80Val substitution as a benign variant. The subcellular localization of Asp191Thrfs*9 suggests a disturbed nuclear import for this mutation. Thus, we consider six of the 10 novel variants as pathogenic mutations accounting for a mutation frequency of 1.1%. Mutation carriers presented mainly with early onset dystonia (<12 years in five of six patients). Symptoms started in an arm or neck and spread to become generalized in three patients or segmental in two patients. Speech was affected in four mutation carriers. In conclusion, THAP1 mutations are rare in unselected dystonia patients and functional analysis is necessary to distinguish between benign variants and pathogenic mutations.
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Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal.
Mov. Disord.
PUBLISHED: 04-06-2011
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The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique "hobby horse gait." Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.
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Homozygous THAP1 mutations as cause of early-onset generalized dystonia.
Mov. Disord.
PUBLISHED: 03-21-2011
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To identify the underlying genetic cause in a consanguineous family with apparently recessively inherited dystonia, we performed genome-wide homozygosity mapping. This revealed 2 candidate regions including the THAP1 gene, where heterozygous mutations cause dystonia 6. A homozygous missense mutation in THAP1 (c.95T>A; p.Leu32His) was found in all 3 affected siblings. Symptoms started in childhood in the legs and became generalized within a few years. Three heterozygous mutation carriers were unaffected. Because THAP1 regulates the expression of the DYT1 gene, we used reporter gene assays to show that DYT1 expression was significantly increased for Leu32His. However, this increase was less pronounced than for other THAP1 mutations that cause dystonia in the heterozygous state. Our data suggest that homozygous THAP1 mutations cause dystonia and may be associated with a less severe dysfunction of the encoded protein compared with heterozygous disease-causing mutations.
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An unusual neurological syndrome of crawling gait, dystonia, pyramidal signs, and limited speech.
Mov. Disord.
PUBLISHED: 03-09-2011
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The purpose of the study was to identify and molecularly characterize a neurological syndrome in a consanguineous Pakistani family.
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Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts.
PLoS ONE
PUBLISHED: 01-11-2011
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PINK1 and Parkin mutations cause recessive Parkinsons disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy.Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrial membrane potential (??) inhibitors or H(2)O(2) resulted in ubiquitination of Mfn1/2 but not of OPA1 or Fis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1 h of treatment. Upon combined inhibition of ?? and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress.For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impair ubiquitination of Mitofusins. In the presence of UPS inhibitors, ubiquitinated Mitofusin is deubiquitinated by the UPS but not degraded, suggesting that the UPS is involved in Mitofusin degradation.
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The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6).
Ann. Neurol.
PUBLISHED: 10-27-2010
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Mutations in THAP1 have been associated with dystonia 6. THAP1 encodes a transcription factor with mostly unknown targets. We tested the hypothesis that THAP1 regulates the expression of DYT1 (TOR1A), another dystonia-causing gene. After characterization of the TOR1A promoter, we demonstrate that THAP1 binds to the core promoter of TOR1A. Further, we report that wild type THAP1 represses the expression of TOR1A, whereas dystonia 6-associated mutant THAP1 results in decreased repression of TOR1A. Our data demonstrate that THAP1 regulates the transcription of TOR1A, suggesting transcriptional dysregulation as a cause of dystonia.
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Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinsons disease.
Mov. Disord.
PUBLISHED: 08-20-2010
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Olfaction is typically impaired in idiopathic Parkinsons disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth-Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 ± 13.5) compared with all other groups (MC 13.8 ± 11.9, NMC 19.6 ± 13.0, controls 33.8 ± 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 ± 92.7). In MC (122.4 ± 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 ± 38.8) were comparable with controls (97.2 ± 61.1). UPSIT and FM scores were correlated in the control (r = -0.305; P = 0.002) and the IPD group (r = -0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1-associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel.
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Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families.
Mov. Disord.
PUBLISHED: 08-06-2010
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The purpose of the study was to delineate clinical and electrophysiological characteristics as well as laryngoscopical and transcranial ultrasound (TCS) findings in THAP1 mutation carriers (MutC). According to recent genetic studies, DYT6 (THAP1) gene mutations are an important cause of primary early-onset dystonia. In contrast to DYT1 mutations, THAP1 mutations are associated with primary early-onset segmental or generalised dystonia frequently involving the craniocervical region and the larynx. Blood samples from twelve individuals of three German families with DYT6 positive index cases were obtained to test for THAP1 mutations. Eight THAP1 MutC were identified. Of these, six (three symptomatic and three asymptomatic) THAP1 MutC could be clinically evaluated. Laryngoscopy was performed to evaluate laryngeal dysfunction in patients. Brainstem echogenicity was investigated in all MutC using TCS. Two of the patients had undergone bilateral pallidal DBS. In all three symptomatic MutC, early-onset laryngeal dystonia was a prominent feature. Laryngeal assessment demonstrated adductor-type dystonia in all of them. On clinical examination, the three asymptomatic MutC also showed subtle signs of focal or segmental dystonia. TCS revealed increased substantia nigra (SN) hyperechogenicity in all MutC. Intraoperative microelectrode recordings under general anesthesia in two of the patients showed no difference between THAP1 and previously operated DYT1 MutC. The presence of spasmodic dysphonia in patients with young-onset segmental or generalised dystonia is a hallmark of DYT6 dystonia. SN hyperechogenicity on TCS may represent an endophenotype in these patients. Pallidal DBS in two patients was unsatisfactory.
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Risk for antipsychotic-induced extrapyramidal symptoms: influence of family history and genetic susceptibility.
Psychopharmacology (Berl.)
PUBLISHED: 07-26-2010
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This study aims to further evaluate the impact of family history of primary movement disorders (FHpMD) and a candidate genetic variant on risk of antipsychotic-induced extrapyramidal symptoms (EPS).
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Mutant Parkin impairs mitochondrial function and morphology in human fibroblasts.
PLoS ONE
PUBLISHED: 07-01-2010
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Mutations in Parkin are the most common cause of autosomal recessive Parkinson disease (PD). The mitochondrially localized E3 ubiquitin-protein ligase Parkin has been reported to be involved in respiratory chain function and mitochondrial dynamics. More recent publications also described a link between Parkin and mitophagy.
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Possible genetic heterogeneity of spinocerebellar ataxia linked to chromosome 15.
Mov. Disord.
PUBLISHED: 07-01-2010
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Autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. We investigated an SCA family from Serbia of Roma ethnic origin; four affected and nine unaffected family members underwent a detailed neurological examination. The presenting symptom in all patients was gait unsteadiness in early adulthood. Additional features included pyramidal signs, depression, and cognitive impairment. The condition follows an autosomal dominant pattern of inheritance. After excluding repeat expansions in nine known SCA genes, a genome-wide linkage analysis with 412 microsatellite markers localized the putative disease gene to a 40.7 cM (42.5 Mb) region on chromosome 15q between markers D15S1006 and D15S116. The maximum model-based multipoint LOD score was 1.75. This region is only 4.3 Mb away from the SCA11 (TTBK2) gene. Accordingly, mutations in TTBK2 were not found, suggesting a second SCA gene on chromosome 15q as cause of this novel form of SCA. In addition, we excluded alterations in two candidate genes in the linked region, namely expansion of a polyglutamine-coding CAG repeat in ARID3B and mutations in SEMA6D.
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Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients.
Hum. Mol. Genet.
PUBLISHED: 05-27-2010
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Mutations in the PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine-threonine kinase, and Parkin, an E3 ubiquitin ligase, are associated with autosomal-recessive forms of Parkinson disease (PD). Both are involved in the maintenance of mitochondrial integrity and protection from multiple stressors. Recently, Parkin was demonstrated to be recruited to impaired mitochondria in a PINK1-dependent manner, where it triggers mitophagy. Using primary human dermal fibroblasts originating from PD patients with various PINK1 mutations, we showed at the endogenous level that (i) PINK1 regulates the stress-induced decrease of endogenous Parkin; (ii) mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of Parkin; (iii) endogenous PINK1 is stabilized on depolarized mitochondria; and (iv) mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin signal and its mitochondrial translocation. Furthermore, we showed that different stressors, depolarizing or non-depolarizing, led to the same effect on detectable Parkin levels and its mitochondrial targeting. Although this effect on Parkin was independent of the mitochondrial membrane potential, we demonstrate a differential effect of depolarizing versus non-depolarizing stressors on endogenous levels of PINK1. Our study shows the necessity to introduce an environmental factor, i.e. stress, to visualize the differences in the interaction of PINK1 and Parkin in mutants versus controls. Establishing human fibroblasts as a suitable model for studying this interaction, we extend data from animal and other cellular models and provide experimental evidence for the generally held notion of PD as a condition with a combined genetic and environmental etiology.
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ATP13A2 variants in early-onset Parkinsons disease patients and controls.
Mov. Disord.
PUBLISHED: 08-26-2009
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Four genes responsible for recessively inherited forms of Parkinsons disease (PD) have been identified, including the recently discovered ATP13A2 (PARK9) gene. Our objective was to investigate the role of this gene in a large cohort of PD patients and controls. We extensively screened all 29 exons of the ATP13A2 coding region in 112 patients with early-onset PD (EOPD; <40 years) of mostly European ethnic origin and of 55 controls. We identified four carriers (3.6%) of novel single heterozygous ATP13A2 missense changes that were absent in controls. Interestingly, the carrier of one of these variants also harbored two mutations in the Parkin gene. None of the carriers had atypical features previously described in patients with two mutated ATP13A2 alleles (Kufor-Rakeb syndrome). Our data suggest that two mutated ATP13A2 alleles are not a common cause of PD. Although heterozygous variants are present in a considerable number of patients, they are-based on this relatively small sample-not significantly more frequent in patients compared to controls.
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Genetic association study of the P-type ATPase ATP13A2 in late-onset Parkinsons disease.
Mov. Disord.
PUBLISHED: 07-28-2009
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A role of ATP13A2 in early-onset Parkinsonism (EOP) has been proposed. Conversely, the contribution of this ATPase to late-onset Parkinsons disease (PD) remains unexplored. We therefore conducted a case-control association study in this age-of-onset group with PD. The initial sample was of German origin and consisted of 220 patients with late-onset PD (mean age of onset 60.1 years) and 232 age-matched unrelated controls. Five single nucleotide polymorphisms (SNPs) covering ATP13A2 and its common haplotypes were genotyped. The overall association results in this sample were negative. Interestingly, gender stratification gave a positive result for SNP rs11203280 (P(UNC) = 0.016) in men. This result could not be reproduced in a replication sample of German and Serbian origin composed of 161 patients with late-onset PD (mean age of onset 51.7 years) and 150 age- and ethnic-matched controls. In conclusion, we found no consistent evidence for an association between ATP13A2 and late-onset PD.
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Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study.
Lancet Neurol
PUBLISHED: 04-01-2009
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DYT6 is a primary, early-onset torsion dystonia; however, unlike in DYT1 dystonia, the symptoms of DYT6 dystonia frequently involve the craniocervical region. Recently, two mutations in THAP1, the gene that encodes THAP (thanatos-associated protein) domain-containing apoptosis-associated protein 1 (THAP1), have been identified as a cause of DYT6 dystonia.
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MDR1 variants and risk of Parkinson disease. Association with pesticide exposure?
J. Neurol.
PUBLISHED: 01-29-2009
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The multidrug resistance protein 1 (MDR1 or ABCB1) gene encodes a P-glycoprotein that protects the brain against neurotoxicants. Certain MDR1 genetic variants are known to compromise the function of this transporter and may thus be associated with Parkinson disease (PD). We therefore conducted a large case-control study investigating the potential relationship between MDR1 variants and PD. We determined the frequency of three MDR1 variants in 599 European PD patients and controls and further stratified the population by ethnicity, age at onset, and exposure to pesticides. We detected no relevant association in either the entire sample, or when separately investigating by ethnic origin or age at onset. However, the distribution of c.3435C/T differed significantly between PD patients exposed to pesticides compared to those non-exposed (odds ratio=4.74; confidence interval=[1.009; 22.306]); p=0.047), suggesting that common MDR1 variants might influence the risk to develop PD in conjunction with exposure to pesticides.
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Frequency of heterozygous Parkin mutations in healthy subjects: need for careful prospective follow-up examination of mutation carriers.
Parkinsonism Relat. Disord.
PUBLISHED: 01-21-2009
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The role of single heterozygous mutations in the putatively recessive Parkin gene in Parkinson disease (PD) is a vividly debated issue, partly caused by the largely unknown frequency of these mutations in healthy individuals. We investigated mutations in all 12 Parkin exons in 356 controls from two European populations including individuals from South Tyrol and Germany. None of the controls carried a homozygous or compound heterozygous mutation. Seventeen carriers of rare heterozygous alterations were detected, of which 13 (13/356; 3.7%) are considered to alter protein structure including four different gene dosage alterations, four missense mutations, and two frameshift mutations. Two of the mutations occurred recurrently in the South Tyrolean population. There was no obvious difference in the mutation frequency between the two populations. One of the presumably healthy mutation carrier was available for re-examination at the age of 67 years. He presented with mild signs of parkinsonism but not fulfilling diagnostic criteria for definite PD. To elucidate the role of heterozygosity is important for genetic testing and counseling of mutation carriers. A detailed clinical prospective and follow-up examination of mutation carriers is required for a better understanding of the role of heterozygous Parkin mutations.
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Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.
Ann. Neurol.
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OBJECTIVE: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia. Ann Neurol 2012.
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Exome sequencing in a family with restless legs syndrome.
Mov. Disord.
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Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found.
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Frequency of the D620N mutation in VPS35 in Parkinson disease.
Arch. Neurol.
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To evaluate the frequency and clinical spectrum of the recently identified p.D620N mutation in the VPS35 gene in Parkinson disease (PD) in an international sample.
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Genetics of Parkinson disease and other movement disorders.
Curr. Opin. Neurol.
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We will review the recent advances in the genetics of Parkinson disease and other movement disorders such as dystonia, essential tremor and restless legs syndrome (RLS).
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Depression and quality of life in monogenic compared to idiopathic, early-onset Parkinsons disease.
Mov. Disord.
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Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early-onset PD cases, 21% of late-onset cases, and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson-associated depression reported fewer feelings of guilt or self-doubt than treated controls, but the occurrence of suicidal ideation was associated with severity of depression only. Social phobia (P = 0.018) and agoraphobia (P = 0.059) were more common in manifesting carriers than in any other group. QoL was decreased in the Parkinson groups, particularly in the early-onset cases (P < 0.001), and QoL correlated with depression in all analyses. In our study, monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further optimized.
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Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples.
Neurology
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Originally, locus symbols (e.g., DYT1) were introduced to specify chromosomal regions that had been linked to a familial disorder with a yet unknown gene. Symbols were systematically assigned in a numerical series to designate mapped loci for a specific phenotype or group of phenotypes. Since the system of designating and using locus symbols was originally established, both our knowledge and our techniques of gene discovery have evolved substantially. The current system has problems that are sources of confusion, perpetuate misinformation, and misrepresent the system as a useful reference tool for a list of inherited disorders of a particular phenotypic class. These include erroneously assigned loci, duplicated loci, missing symbols, missing loci, unconfirmed loci in a consecutively numbered system, combining causative genes and risk factor genes in the same list, and discordance between phenotype and list assignment. In this article, we describe these problems and their impact, and propose solutions. The system could be significantly improved by creating distinct lists for clinical and research purposes, creating more informative locus symbols, distinguishing disease-causing mutations from risk factors, raising the threshold of evidence prior to assigning a locus symbol, paying strict attention to the predominant phenotype when assigning symbols lists, and having a formal system for reviewing and continually revising the list that includes input from both clinical and genetics experts.
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