References of "Hagenah, Johann"
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See detailGenome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?
Lohmann, Katja; Schmidt, Alexander; Schillert, Arne et al

in Movement disorders : official journal of the Movement Disorder Society (2014), 29(7), 921-7

Musician's 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 ... [more ▼]

Musician's 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 writer's 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 < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 x 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 x 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 x 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (lambda = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients. [less ▲]

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See detailPhosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous Parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cell-derived neurons.
Rakovic, Aleksandar; Shurkewitsch, Katharina; Seibler, Philip et al

in The Journal of biological chemistry (2013), 288(4), 2223-37

Mutations in the E3 ubiquitin ligase Parkin and the mitochondrial PTEN-induced putative kinase 1 (PINK1) have been identified to cause autosomal recessive forms of familial Parkinson disease, with PINK1 ... [more ▼]

Mutations in the E3 ubiquitin ligase Parkin and the mitochondrial PTEN-induced putative kinase 1 (PINK1) have been identified to cause autosomal recessive forms of familial Parkinson disease, with PINK1 functioning upstream of Parkin in a pathway important for the maintenance of mitochondrial function and morphology. Upon the loss of the mitochondrial membrane potential, Parkin translocates to mitochondria in a PINK1-dependent manner to ubiquitinate mitochondrial proteins. Parkin-mediated polyubiquitination of outer mitochondrial membrane (OMM) proteins recruits the ubiquitin- and LC3-binding adaptor protein p62 to mitochondria and induces mitophagy. Although previous studies examined mitophagy in established cell lines through overexpression approaches, there is an imperative to study the role of endogenous Parkin and PINK1 in human-derived and biologically relevant cell models. Here, we demonstrate in human primary fibroblasts and induced pluripotent stem-derived neurons from controls and PINK1 mutation carriers that endogenous levels of Parkin are not sufficient to initiate mitophagy upon loss of the mitochondrial membrane potential, caused by its (self-)ubiquitination, followed by degradation via the ubiquitin proteasome system. Next, we showed differential PINK1-dependent, Parkin-mediated ubiquitination of OMM proteins, which is Parkin dose-dependent and affects primarily OMM proteins of higher molecular mass. In contrast to the situation fibroblasts, we did not detect mitophagy in induced pluripotent stem-derived neurons even upon overexpression of Parkin. Taken together, our data demonstrate that mitophagy differs between human non-neuronal and neuronal cells and between "endogenous" and "Parkin-overexpressing" cellular models. [less ▲]

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See detailMortalin mutations are not a frequent cause of early-onset Parkinson disease.
Freimann, Karen; Zschiedrich, Katja; Bruggemann, Norbert et al

in Neurobiology of aging (2013), 34(11), 269419-20

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 48 (1 UL)
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See detailProminent psychiatric comorbidity in the dominantly inherited movement disorder myoclonus-dystonia.
Weissbach, Anne; Kasten, Meike; Grünewald, Anne UL et al

in Parkinsonism & related disorders (2013), 19(4), 422-5

BACKGROUND: Neurological and psychiatric disorders show clinical overlap suggesting a shared pathophysiological background. We evaluated myoclonus-dystonia, a monogenic movement disorder as a disease ... [more ▼]

BACKGROUND: Neurological and psychiatric disorders show clinical overlap suggesting a shared pathophysiological background. We evaluated myoclonus-dystonia, a monogenic movement disorder as a disease model for inherited psychopathology. METHOD: We investigated 12 SGCE mutation carriers using standardized neurological and psychiatric examinations to assign DSM-IV diagnoses. Furthermore, we analyzed all studies in the Medline database which included psychiatric information on SGCE mutation-positive patients. RESULTS: Of our twelve SGCE mutation carriers, 10 were older than 16 years. Two of them (20%) reported psychiatric diagnoses before our examination, which resulted in at least one psychiatric diagnosis in seven (70%) patients, most frequently anxiety (60%), depression (30%) or both. Substance abuse was observed in 20%, whereas obsessive-compulsive disorders were absent. One mutation carrier showed Axis 2 features. In the literature analysis, the ten studies using standardized tools covering DSM-IV criteria reported prevalences similar to those in our sample. This was three times the frequency of psychiatric disorders detected in 13 studies using clinical history or patient report only. CONCLUSION: About two thirds of SGCE mutation carriers develop psychiatric comorbidity and >80% are previously undiagnosed. [less ▲]

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See detailTwo faces of the same coin: benign familial infantile seizures and paroxysmal kinesigenic dyskinesia caused by PRRT2 mutations.
Schmidt, Alexander; Kumar, Kishore R.; Redyk, Katharina et al

in Archives of neurology (2012), 69(5), 668-70

Detailed reference viewed: 46 (5 UL)
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See detailBiological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.
Grünewald, Anne UL; Breedveld, Guido J.; Lohmann-Hedrich, Katja et al

in Neurogenetics (2007), 8(2), 103-9

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T ... [more ▼]

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation. [less ▲]

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See detailAutosomal dominant myoclonus-dystonia and Tourette syndrome in a family without linkage to the SGCE gene.
Orth, Michael; Djarmati, Ana; Baumer, Tobias et al

in Movement disorders : official journal of the Movement Disorder Society (2007), 22(14), 2090-6

The objective of this study was to report clinical details and results of genetic testing for mutations in the epsilon-sarcoglycan (SGCE) gene, the Slit and Trk-like 1 (SLITRK1) gene and for linkage to ... [more ▼]

The objective of this study was to report clinical details and results of genetic testing for mutations in the epsilon-sarcoglycan (SGCE) gene, the Slit and Trk-like 1 (SLITRK1) gene and for linkage to the DYT15, DYT1, and DRD2 gene loci in a family with autosomal dominant myoclonus-dystonia (M-D) and Gilles de la Tourette syndrome (GTS). Fourteen family members, from three generations, underwent a detailed clinical assessment and donated DNA samples. The SGCE and the SLITRK1 gene were sequenced and investigated by gene dosage analysis in selected family members. Linkage to the SGCE, DYT15, DYT1, DRD2, and SLITRK1 loci was also tested. RESULTS: We included three healthy and 11 affected family members with M-D (n = 3), dystonia alone (n = 2), GTS (n = 1), tics (n = 1) or a combination of these with obsessive compulsive disorder (OCD) (M-D + OCD: n = 2; dystonia+OCD: n = 1; M-D + GTS + OCD: n = 1). There was no linkage to the SGCE, DYT15, DYT1 or DRD2 loci. No changes were found in the SLITRK1 gene. The presence of both M-D and GTS in one family, in which all known M-D loci and a recently discovered GTS locus were excluded, suggests a novel susceptibility gene for both M-D and GTS. [less ▲]

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See detailClinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?
Hedrich, Katja; Hagenah, Johann; Djarmati, Ana et al

in Archives of neurology (2006), 63(6), 833-8

BACKGROUND: Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous ... [more ▼]

BACKGROUND: Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear. OBJECTIVE: To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W). DESIGN: Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating. SETTINGS: University of Lubeck. PARTICIPANTS: Twenty family members. MAIN OUTCOME MEASURES: The PINK1 genotype and PD status of all family members. RESULTS: The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers. CONCLUSIONS: Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling. [less ▲]

Detailed reference viewed: 47 (4 UL)