CLINICOPATHOLOGIC STUDY OF A
 SNCA
 GENE DUPLICATION PATIENT WITH PARKINSON DISEASE AND DEMENTIA

Obi, Tomokazu; Nishioka, Kenya; Ross, Owen A.; Terada, Tatsuhiro; Yamazaki, Kunio; Sugiura, Akira; Takanashi, Masashi; Mizoguchi, Koichi; Mori, Hideo; Mizuno, Y; Hattori, Nobutaka

doi:10.1212/01.wnl.0000299387.59159.db

Cited by 79 publications

(55 citation statements)

References 9 publications

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“…It is sometimes associated with tauopathy [10] that resembles argyrophilic grain disease, a medial temporal tauopathy that increases in frequency with age [11] and can also present with amnestic mild cognitive impairment [12] . Focal neuronal loss and gliosis in the hippocampus can be seen in other degenerative disorders, such as Lewy body disease, but the distribution is different, being most severe in CA2/3 [13,14] .…”

Section: Introductionmentioning

confidence: 99%

Common Variant in GRN Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly

Dickson

Baker

Rademakers³

2010

Neurodegener Dis

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Background: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. Objective: The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. Methods: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods. Results: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele. Conclusion: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.

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Section: Introductionmentioning

confidence: 99%

Common Variant in GRN Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly

Dickson

Baker

Rademakers³

2010

Neurodegener Dis

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“…The subsequent identification of SNCA locus duplications lead to the additional observations of whole-gene duplications and triplications of variable genomic lengths [Chartier-Harlin et al, 2004;Farrer et al, 2004;Fuchs et al, 2007;Ibanez et al, 2004;Ikeuchi et al, 2008;Nishioka et al, 2006;Obi et al, 2008]. There was, however, no evidence that overexpression of other genes located in the repeated regions contributed to the PD phenotype in duplication or triplication carriers .…”

Section: Introductionmentioning

confidence: 99%

“…There was, however, no evidence that overexpression of other genes located in the repeated regions contributed to the PD phenotype in duplication or triplication carriers . Most studies showed that SNCA dosage influenced clinical expression of PD, with PD with dementia (PDD) being more common in SNCA duplication carriers and dementia with Lewy bodies (DLB) in SNCA triplication carriers [Chartier-Harlin et al, 2004;Farrer et al, 2004;Fuchs et al, 2007;Ibanez et al, 2004;Ikeuchi et al, 2008;Nishioka et al, 2006;Obi et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

et al. 2009

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The relative contribution of simple mutations and copy number variations (CNVs) in SNCA, PARK2, PINK1, PARK7, and LRRK2 to the genetic etiology of Parkinson disease (PD) is still unclear because most studies did not completely analyze each gene. In a large group of Belgian PD patients (N = 310) and control individuals (N = 270), we determined the mutation frequency of both simple mutations and CNVs in these five PD genes, using direct sequencing, multiplex amplicon quantification (MAQ), and real-time PCR assays. Overall, we identified 14 novel heterozygous variants, of which 11 were absent in control individuals. We observed eight PARK2 (multiple) exon multiplications in PD patients and one exon deletion in a control individual. Furthermore, we identified one SNCA whole-gene duplication. The PARK2 and LRRK2 mutation frequencies in Belgian PD patients were similar to those reported in other studies. However, at this stage the true pathogenic nature of some heterozygous mutations in recessive genes remains elusive. Furthermore, though mutations is SNCA, PINK1, and PARK7 are rare, our identification of a SNCA duplication confirmed that screening of these genes remains meaningful.

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“…One patient presented with a severe clinical course with no efficacy for levodopa therapy. He progressed to Hoehn and Yahr stage V in a few years and at autopsy demonstrated features similar to DLB (Obi et al, 2008). In addition, we also detected five asymptomatic carriers over 65 years old.…”

Section: Snca Triplication and Duplication In Hereditary Pdmentioning

confidence: 52%

SNCA Gene Multiplication: A Model Mechanism of Parkinson Disease

Nishioka¹,

Ross²

2011

Gene Duplication

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CLINICOPATHOLOGIC STUDY OF A SNCA GENE DUPLICATION PATIENT WITH PARKINSON DISEASE AND DEMENTIA

Cited by 79 publications

References 9 publications

Common Variant in <i>GRN</i> Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly

Common Variant in <i>GRN</i> Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly

Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

SNCA Gene Multiplication: A Model Mechanism of Parkinson Disease

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