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Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations

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Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations

Auteurs : N. Pankratz ; D Kissell ; M Pauciulo ; C Halter ; A. Rudolph ; R Pfeiffer ; K Marder ; T. Foroud ; W Nichols

Source :

Neurology [ 0028-3878 ] ; 2009.

RBID : PMC:2715211

English descriptors

KwdEn :
- Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Base Sequence (genetics), DNA Mutational Analysis, Female, Gene Deletion, Gene Dosage (genetics), Gene Frequency (genetics), Genetic Markers (genetics), Genetic Predisposition to Disease (genetics), Genetic Testing, Genotype, Haplotypes (genetics), Humans, Male, Middle Aged, Mutation (genetics), Parkinson Disease (genetics), Parkinson Disease (metabolism), Parkinson Disease (physiopathology), Point Mutation (genetics), Risk Factors, Ubiquitin-Protein Ligases (genetics), Young Adult.
MESH :
- chemical , genetics : Genetic Markers, Ubiquitin-Protein Ligases.
- genetics : Base Sequence, Gene Dosage, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, Mutation, Parkinson Disease, Point Mutation.
- metabolism : Parkinson Disease.
- physiopathology : Parkinson Disease.
- Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, DNA Mutational Analysis, Female, Gene Deletion, Genetic Testing, Genotype, Humans, Male, Middle Aged, Risk Factors, Young Adult.

Abstract

Objective:

Mutations in both alleles of parkin have been shown to result in Parkinson disease (PD). However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for PD.

Methods:

We performed comprehensive dosage and sequence analysis of all 12 exons of parkin in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single parkin mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 parkin mutations.

Results:

We identified 55 independent patients with PD with at least 1 parkin mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, p = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at ≤45 years) compared with those with no parkin mutations (10%, p = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at ≤45 years, p = 0.06).

Conclusions:

Parkin haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset.

GLOSSARY

ADL

= Activities of Daily Living;

GDS

= Geriatric Depression Scale;

MLPA

= multiplex ligation-dependent probe amplification;

MMSE

= Mini-Mental State Examination;

= Parkinson disease;

UPDRS

= Unified Parkinson’s Disease Rating Scale.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715211

DOI: 10.1212/WNL.0b013e3181af7a33
PubMed: 19636047
PubMed Central: 2715211

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PMC:2715211

Le document en format XML

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 dosage mutations have greater pathogenicity in familial PD than simple sequence mutations</title>
<author><name sortKey="Pankratz, N" sort="Pankratz, N" uniqKey="Pankratz N" first="N" last="Pankratz">N. Pankratz</name>
</author>
<author><name sortKey="Kissell, D K" sort="Kissell, D K" uniqKey="Kissell D" first="D" last="Kissell">D Kissell</name>
</author>
<author><name sortKey="Pauciulo, M W" sort="Pauciulo, M W" uniqKey="Pauciulo M" first="M" last="Pauciulo">M Pauciulo</name>
</author>
<author><name sortKey="Halter, C A" sort="Halter, C A" uniqKey="Halter C" first="C" last="Halter">C Halter</name>
</author>
<author><name sortKey="Rudolph, A" sort="Rudolph, A" uniqKey="Rudolph A" first="A" last="Rudolph">A. Rudolph</name>
</author>
<author><name sortKey="Pfeiffer, R F" sort="Pfeiffer, R F" uniqKey="Pfeiffer R" first="R" last="Pfeiffer">R Pfeiffer</name>
</author>
<author><name sortKey="Marder, K S" sort="Marder, K S" uniqKey="Marder K" first="K" last="Marder">K Marder</name>
</author>
<author><name sortKey="Foroud, T" sort="Foroud, T" uniqKey="Foroud T" first="T" last="Foroud">T. Foroud</name>
</author>
<author><name sortKey="Nichols, W C" sort="Nichols, W C" uniqKey="Nichols W" first="W" last="Nichols">W Nichols</name>
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 dosage mutations have greater pathogenicity in familial PD than simple sequence mutations</title>
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<author><name sortKey="Kissell, D K" sort="Kissell, D K" uniqKey="Kissell D" first="D" last="Kissell">D Kissell</name>
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<author><name sortKey="Halter, C A" sort="Halter, C A" uniqKey="Halter C" first="C" last="Halter">C Halter</name>
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<author><name sortKey="Rudolph, A" sort="Rudolph, A" uniqKey="Rudolph A" first="A" last="Rudolph">A. Rudolph</name>
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<author><name sortKey="Pfeiffer, R F" sort="Pfeiffer, R F" uniqKey="Pfeiffer R" first="R" last="Pfeiffer">R Pfeiffer</name>
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<author><name sortKey="Marder, K S" sort="Marder, K S" uniqKey="Marder K" first="K" last="Marder">K Marder</name>
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<author><name sortKey="Foroud, T" sort="Foroud, T" uniqKey="Foroud T" first="T" last="Foroud">T. Foroud</name>
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<author><name sortKey="Nichols, W C" sort="Nichols, W C" uniqKey="Nichols W" first="W" last="Nichols">W Nichols</name>
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<series><title level="j">Neurology</title>
<idno type="ISSN">0028-3878</idno>
<idno type="e-ISSN">1526-632X</idno>
<imprint><date when="2009">2009</date>
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<term>Adult</term>
<term>Age of Onset</term>
<term>Aged</term>
<term>Aged, 80 and over</term>
<term>Base Sequence (genetics)</term>
<term>DNA Mutational Analysis</term>
<term>Female</term>
<term>Gene Deletion</term>
<term>Gene Dosage (genetics)</term>
<term>Gene Frequency (genetics)</term>
<term>Genetic Markers (genetics)</term>
<term>Genetic Predisposition to Disease (genetics)</term>
<term>Genetic Testing</term>
<term>Genotype</term>
<term>Haplotypes (genetics)</term>
<term>Humans</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Mutation (genetics)</term>
<term>Parkinson Disease (genetics)</term>
<term>Parkinson Disease (metabolism)</term>
<term>Parkinson Disease (physiopathology)</term>
<term>Point Mutation (genetics)</term>
<term>Risk Factors</term>
<term>Ubiquitin-Protein Ligases (genetics)</term>
<term>Young Adult</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Genetic Markers</term>
<term>Ubiquitin-Protein Ligases</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Base Sequence</term>
<term>Gene Dosage</term>
<term>Gene Frequency</term>
<term>Genetic Predisposition to Disease</term>
<term>Haplotypes</term>
<term>Mutation</term>
<term>Parkinson Disease</term>
<term>Point Mutation</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Parkinson Disease</term>
</keywords>
<keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Parkinson Disease</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adolescent</term>
<term>Adult</term>
<term>Age of Onset</term>
<term>Aged</term>
<term>Aged, 80 and over</term>
<term>DNA Mutational Analysis</term>
<term>Female</term>
<term>Gene Deletion</term>
<term>Genetic Testing</term>
<term>Genotype</term>
<term>Humans</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Risk Factors</term>
<term>Young Adult</term>
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<front><div type="abstract" xml:lang="en"><sec><title>Objective:</title>
<p>Mutations in both alleles of <italic>parkin</italic>
 have been shown to result in Parkinson disease (PD). However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 <italic>parkin</italic>
 alleles) increases the risk for PD.</p>
</sec>
<sec><title>Methods:</title>
<p>We performed comprehensive dosage and sequence analysis of all 12 exons of <italic>parkin</italic>
 in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single <italic>parkin</italic>
 mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 <italic>parkin</italic>
 mutations.</p>
</sec>
<sec><title>Results:</title>
<p>We identified 55 independent patients with PD with at least 1 <italic>parkin</italic>
 mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, <italic>p</italic>
 = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, <italic>p</italic>
 = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at ≤45 years) compared with those with no <italic>parkin</italic>
 mutations (10%, <italic>p</italic>
 = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at ≤45 years, <italic>p</italic>
 = 0.06).</p>
</sec>
<sec><title>Conclusions:</title>
<p><italic>Parkin</italic>
 haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset.</p>
</sec>
<sec><title>GLOSSARY</title>
<def-list list-type="abr"><def-item><term><bold>ADL</bold>
</term>
<def><p> = Activities of Daily Living; </p>
</def>
</def-item>
<def-item><term><bold>GDS</bold>
</term>
<def><p> = Geriatric Depression Scale; </p>
</def>
</def-item>
<def-item><term><bold>MLPA</bold>
</term>
<def><p> = multiplex ligation-dependent probe amplification; </p>
</def>
</def-item>
<def-item><term><bold>MMSE</bold>
</term>
<def><p> = Mini-Mental State Examination; </p>
</def>
</def-item>
<def-item><term><bold>PD</bold>
</term>
<def><p> = Parkinson disease; </p>
</def>
</def-item>
<def-item><term><bold>UPDRS</bold>
</term>
<def><p> = Unified Parkinson’s Disease Rating Scale.</p>
</def>
</def-item>
</def-list>
</sec>
</div>
</front>
</TEI>
</record>

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Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations

Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations

Source :

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Links to Exploration step

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki