Parkin dosage mutations in patients with early-onset sporadic and familial Parkinson's disease in Chinese: An independent pathogenic role

Wang, Chaodong; Ma, Heng; Feng, Xiaoyan; Xie, Shu; Chan, Piu

doi:10.1016/j.brainres.2010.08.060

Cited by 13 publications

(17 citation statements)

References 37 publications

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“…However, pathogenicities of parkin mutations, especially those in heterozygotes, remain controversial, possibly due to confusions caused by the "mixed" effects of all types of mutations (Wang et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Although PD causative mutations of parkin are usually homozygous or compound heterozygous, previous studies have hypothesized that the heterozygous mutations may cause haploinsufficiency of the gene and increase the risk for PD (Foroud et al 2003;Sun et al 2006;Wang et al 2010). Parkin is particularly susceptible to whole exon deletions and duplications; it is therefore imperative to consider exon dosage mutations when performing mutation screening of parkin (Lücking et al 2000;Periquet et al 2003).…”

Section: Parkinson Protein 2 (Park2 Parkin) Genementioning

confidence: 99%

“…Parkin is particularly susceptible to whole exon deletions and duplications; it is therefore imperative to consider exon dosage mutations when performing mutation screening of parkin (Lücking et al 2000;Periquet et al 2003). The results of Wang et al (2010), showed clearly that most (>60%) of the dosage parkin mutations identified in both the familial and sporadic EOPD cases were heterozygotes, and that heterozygous dosage mutations alone can increase the overall risk for development of EOPD, especially of AREP (autosomal-recessive early-onset parkinsonism) subjects (p = 0.004). Moreover, the carrier status of dosage mutations has significant impact on the clinical features such as age at onset, characteristics of initial signs, and later complications in both AREP and sporadic EOPD patients.…”

Section: Parkinson Protein 2 (Park2 Parkin) Genementioning

confidence: 99%

“…However, the dosage heterozygotes may not directly lead to PD because there were members in AREP families for dosage heterozygotes who were not affected. Other mutations such as a second point mutation may be needed to constitute a complete genetic contribution to the disease (Wang et al 2010). …”

Section: Parkinson Protein 2 (Park2 Parkin) Genementioning

confidence: 99%

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Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Bognár¹,

Baldovič²,

Benetin³

et al. 2013

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Abstract. Parkinson disease (PD) is a chronic neurodegenerative movement disorder characterized by selective loss of nigrostriatal dopaminergic neurons and formation of Lewy bodies. Clinical manifestations include motor impairments involving tremor, bradykinesia, postural instability and rigidity.Using dHPLC method we screened exons 31, 35, 41, 48 of the Leucine-rich repeat kinase 2 (LRRK2) gene and exons 2, 6 and 7 of Parkinson protein 2 (parkin, PARK2) genes in a cohort of 216 consecutive, unrelated Slovak patients with familial or sporadic PD, including early and late onset. By this means we aimed to detect the most common pathogenic mutations within LRRK2 (Arg1441Cys, Arg1441Gly, Arg1628Pro, Tyr1699Cys, Gly2019Ser, Ile2020Thr, Gly2385Arg) and parkin genes responsible for late and early onset forms of disease, respectively. However, none of these mutations was identified in our cohort. Heterozygous point mutation p.Arg275Trp in exon 7 of parkin gene was identified in one patient with age at onset 61 years. Furthermore, we observed the presence of one exonic (LRRK2 ex 48: 7155A>G) and eight intronic polymorphisms (in LRRK2: IVS35+23T>A, IVS47-91insGCCAT, IVS47-91insGCAT, IVS47-41A>G, IVS47-9delT, IVS47-20C>T, IVS47-90A>G, in parkin: IVS2+25T>C), three of which were novel.

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Section: Discussionmentioning

confidence: 99%

Section: Parkinson Protein 2 (Park2 Parkin) Genementioning

confidence: 99%

Section: Parkinson Protein 2 (Park2 Parkin) Genementioning

confidence: 99%

Section: Parkinson Protein 2 (Park2 Parkin) Genementioning

confidence: 99%

See 2 more Smart Citations

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Bognár¹,

Baldovič²,

Benetin³

et al. 2013

gpb

View full text Add to dashboard Cite

show abstract

“…For this reason, more than 200 putative pathogenic mutations have been reported worldwide, affecting numerous ethnic populations [33,35,59,[64][65][66][67][68][69][70][71][72][73][74][75][76][77]. The PARK2 mutation spectrum includes homozygous or compound heterozygous missense and nonsense point mutations, as well as several exon rearrangements (both duplications and deletions) involving all 12 exons and the promoter region.…”

Section: Park2mentioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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Han Chinese family with early‐onset Parkinson's disease carries novel compound heterozygous mutations in the PARK2 gene

Huang

Gao

et al. 2019

Brain and Behavior

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Purpose To identify deletions, duplications, and point mutations in 55 previously reported genes associated with Parkinson's disease (PD) and certain genes associated with tremor, spinocerebellar ataxia, and dystonia in a Han Chinese pedigree with early‐onset Parkinson's disease (EOPD). Patients and Methods Clinical examinations and genomic analyses were performed on six subjects belonging to three generations of a Han Chinese family. Target region capture and high‐throughput sequencing were used to screen these genes associated with PD, tremor, spinocerebellar ataxia, and dystonia. The multiplex ligation‐dependent probe amplification (MLPA) method was applied to detect rearrangements in PARK2 exons. Direct Sanger sequencing of samples from all subjects further verified the detected abnormal PRKRA, SPTBN2, and ATXN2 gene fragments. Results Two family members were diagnosed with PD based on the clinical manifestations, imaging analyses. PARK2 gene heterozygous deletion of exon 3 and heterozygous duplication of exon 6 were identified in them (II‐3 and 4). A single heterozygous deletion of exon 3 in PARK2 was detected in II‐5 and III‐10. A single duplication of exon 6 in PARK2 was detected in I1. Both the heterozygous mutation c.2834G>A (p. R945H) in exon 16 and the heterozygous mutation c.1924 C>T (p. R642W) in exon 14 of the SPTBN2 gene were identified in II‐3, II‐4, and III‐10. The heterozygous mutation c.2989 C>T (p. R997X) in exon 24 of the ATXN2 gene was detected in II‐4 and II‐5, and the heterozygous mutation c.170 C>A (p. S57Y) in exon 2 of the PRKRA gene was detected in II‐3, II‐4, and III‐10. Other mutations in some genes associated with PD, tremor, spinocerebellar ataxia, and dystonia were not detected. Conclusions Novel compound heterozygous mutations were identified in a Han Chinese pedigree and might represent a cause of EOPD.

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Parkin dosage mutations in patients with early-onset sporadic and familial Parkinson's disease in Chinese: An independent pathogenic role

Cited by 13 publications

References 37 publications

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Han Chinese family with early‐onset Parkinson's disease carries novel compound heterozygous mutations in the PARK2 gene

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