Frequency of heterozygous Parkin mutations in healthy subjects: Need for careful prospective follow-up examination of mutation carriers

Brüggemann, Norbert; Mitterer, Manfred; Lanthaler, Andrea Judith; Djarmati, Ana; Hagenah, Johann; Wiegers, Karin; Winkler, Susen; Pawlack, Heike; Lohnau, Thora; Pramstaller, Peter P.; Klein, Christine; Lohmann, Katja

doi:10.1016/j.parkreldis.2008.11.014

Cited by 38 publications

(31 citation statements)

References 21 publications

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“…The main difference between our data and most other published datasets is in the controls. The frequency of PARK2 mutation in our controls is higher than most, but is in line with Lincoln et al 20 and Bruggemann et al, 21 who, like us, genotyped controls comprehensively. Most other studies performed detailed genotyping in patients and screened control subjects only for the mutations found in patients; thus, we suspect, missed the mutations that might have been present in controls but not in patients.…”

Section: Figure 3 Moving Average Plots Of Park2 Mutation Frequency Assupporting

confidence: 91%

“…Most other studies performed detailed genotyping in patients and screened control subjects only for the mutations found in patients; thus, we suspect, missed the mutations that might have been present in controls but not in patients. The 3 studies that genotyped controls comprehensively had sample sizes of 192, 20 356, 21 and 1,686 (this study), and all 3 report 3%-4% of controls carrying heterozygous PARK2 mutations. A study of familial PD, however, found no CNV mutations in 263 control subjects, which was significant compared to their patient population.…”

Section: Figure 3 Moving Average Plots Of Park2 Mutation Frequency Asmentioning

confidence: 99%

“…The majority of positive results are heterozygous and difficult for clinicians to interpret because whether having one mutation can cause, increase risk, or accelerate onset of Parkinson disease (PD) is unknown. [9][10][11][12][13][14][15][16][17][18][19][20][21] The second aim of our study was to determine, conclusively, if heterozygous mutations are associated with PD. We designed this study specifically to address this question, and to that end, amassed a large sample size to ensure analytic power, analyzed the coding regions for all types of variations, and importantly, used the same rigorous mutation analysis and validation methods in control subjects as in patients.…”

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confidence: 99%

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A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2

Kay¹,

Stevens²,

Hamza³

et al. 2010

Neurology

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Objectives: To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study. Methods:We studied 1,686 control subjects (mean age 66.1 Ϯ 13.1 years) and 2,091 patients with PD (mean onset age 58.3 Ϯ 12.1 years). We tested for PARK2 deletions/multiplications/ copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake.Results: A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1-4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2-9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p ϭ 0.89) or earlier onset of PD (64.7 Ϯ 8.6 heterozygous vs 58.5 Ϯ 11.8 normal). Conclusions:This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD. Neurology

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Section: Figure 3 Moving Average Plots Of Park2 Mutation Frequency Assupporting

confidence: 91%

Section: Figure 3 Moving Average Plots Of Park2 Mutation Frequency Asmentioning

confidence: 99%

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confidence: 99%

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A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2

Kay¹,

Stevens²,

Hamza³

et al. 2010

Neurology

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“…18,19,22,23 The possibility that a single mutated allele in a gene can be cause of disease when usually two mutated alleles are causative has been considered for some neurologic disorders, such as for Parkinson's disease with respect to PARKN and for some myopathies such as limb-girdle muscular dystrophy with respect to TTN. [24][25][26][27] The case of SOD1 mutations with respect to amyotrophic lateral sclerosis, which like BVVLS is a motor neuron disorder, is also interesting. SOD1 mutations are usually observed in amyotrophic lateral sclerosis families that exhibit autosomal dominant inheritance.…”

Section: Four Novel Mutations In the Known Bvvls-causing Gene C20orf54mentioning

confidence: 99%

Four novel C20orf54 mutations identified in Brown–Vialetto–Van Laere syndrome patients

et al. 2012

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“…While the implications of heterozygous mutations in PD cannot be conclusively determined, previous data point to a role as a susceptibility factor that is able to cause at least subtle signs of PD later in life. Therefore, they suggested to perform further prospective studies in older controls, in conjunction with a careful neurological examination, in order to elucidate the clinical relevant question of how many of them will eventually develop PD (Brüggemann et al 2009). Thus, the control study requires large control group and long follow up of potentially identified mutation carriers, which was not possible in our pilotal study.…”

Section: Discussionmentioning

confidence: 99%

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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Frequency of heterozygous Parkin mutations in healthy subjects: Need for careful prospective follow-up examination of mutation carriers

Cited by 38 publications

References 21 publications

A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2

A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2

Four novel C20orf54 mutations identified in Brown–Vialetto–Van Laere syndrome patients

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

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