The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism

Hedrich, Katja; Kann, Martin; Lanthaler, Andrea Judith; Dalski, Andreas; Eskelson, Cordula; Landt, Olfert; Schwinger, E.; Vieregge, P.; Lang, Anthony E.; Breakefield, Xandra O.; Ozelius, Laurie J.; Pramstaller, Peter P.; Klein, Christine

doi:10.1093/hmg/10.16.1649

Cited by 140 publications

(161 citation statements)

References 22 publications

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“…This technique was previously demonstrated to detect accurately Parkin mutations in a large number of patients at much higher frequencies. 6,27,28 With regard to the DJ-1 gene, recent studies demonstrated a mutation frequency between 1 and 2% among EOP patients. 7,8,15,16 Only two of the published investigations included testing for gene dosage alterations and, as expected, revealed higher mutation rates (2 versus 1%).…”

Section: Discussionmentioning

confidence: 99%

“…The diagnosis of PD was based on the UK Brain Bank diagnostic criteria (with the exception that positive family history was not regarded an exclusion criterion). 20 6 In all, 100 chromosomes of Italian and 100 chromosomes of German control individuals were screened for the presence of the novel mutations and the novel polymorphism. The mean age of the controls at the time of the blood collection was 52.2714.3 years.…”

Section: Patientsmentioning

confidence: 99%

“…3,5 -9 The latter type of mutations is only detectable upon gene dosage analysis. 6 For the recently identified PINK1 gene, only point mutations and one four-nucleotide insertion have been reported to date. 2,10 -14 While the frequency of Parkin mutations in EOP patients has been estimated at 10 -25%, 5 and DJ-1 mutations account for 1% 15,16 to 2% 7,8 of the tested EOP cases, the frequency of mutations in PINK1 still remains to be accurately determined.…”

Section: Introductionmentioning

confidence: 99%

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PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism

et al. 2005

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Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.275.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/ dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.279.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G4A), and two patients had known Parkin mutations (heterozygous c.734A4T and c.924C4T; heterozygous c.924C4T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A4T) and four novel PINK1 changes of unknown pathogenic significance (À21G/A; IVS1 þ 97A/G; IVS3 þ 38_40delTTT; c.852C4T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.

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Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism

et al. 2005

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“…This points to disease-causing DNA changes localized in untranslated regions. In addition, deletions or duplications of the complete gene or single exons are not seen by the SSCP procedure but may be important in mutational analyses (Hedrich et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism

et al. 2004

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Oculocutaneous albinism (OCA) in man may be caused by mutations within the tyrosinase gene (TYR) resulting in OCA1. Analysing patients with recessively inherited albinism we found DNA variations in 82 unrelated individuals. 53 out of 78 mutations and polymorphisms revealed by this study are not published previously. The changes include 68 nucleotide substitutions resulting in amino acid changes, stop mutations and polymorphisms as well as four nucleotide insertions and six deletions. Furthermore, we found an accumulation of three to five mutations in 17 patients with OCA1.

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“…Fluorescence was measured during the 551C step. Product concentration was calculated as described 5 and…”

Section: Mutation Analysismentioning

confidence: 99%

Extension of the mutation spectrum in Friedreich's ataxia: detection of an exon deletion and novel missense mutations

et al. 2004

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Friedreich's ataxia (FRDA), the most common autosomal recessively inherited ataxia, is due to a homozygous GAA triplet repeat expansion in the first intron of the FRDA gene in about 96% of patients. Approximately 4% of FRDA patients are compound heterozygotes with a GAA repeat expansion in one allele and a point mutation in the coding region of the second allele. To reinvestigate the mutation spectrum, we searched for mutations including exon deletions in six patients heterozygous for the GAA repeat expansion and found two unknown missense mutations, p.Asn146Lys and p.Leu186Arg, in trans to the expanded FRDA allele. Interestingly, we detected a heterozygous 2776 bp deletion including exon 5a in one of our patients. This deletion removes 50 of the 210 residues of the frataxin. Furthermore, since no FRDA case with two-point mutations is known, we screened eight patients with FRDA phenotype but GAA alleles within the normal range but did not reveal a mutation within the FRDA gene. In addition, DNA polymorphisms have been found in four out of 100 control individuals in this study.

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The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism

Cited by 140 publications

References 22 publications

PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism

PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism

Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism

Extension of the mutation spectrum in Friedreich's ataxia: detection of an exon deletion and novel missense mutations

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