ERANET 1 NEURON 3: Identification of copy number variants in familial and pathologically proven PD

Lead Research Organisation: University College London

Abstract

One of the major initial impacts of the human genome project was how little we understood about genomic diversity. Over the past 2-3 years it has become clear that there is tremendous variation in the numbers of copies of a large proportion of the human genome. There are some striking examples of copy numbers leading to human disease. The best characterised in neurological disease is the rearrangements around PMP22 giving rise to CMT1a and hereditary liability to pressure palsies. In Parkinson’s disease, of the currently identified genes,
rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-synuclein duplication or triplication is the commonest mutational mechanism. Copy number variation (CNVs) can be considered in 2 broad ways. First there are rare occurrences (as above) where the duplication or deletion of genomic region may lead to a highly penetrant ‘mendelian’ form of disease. In the second, there is the potential role of ‘common’ rearrangements in susceptibility to disease. In the case of PD the rearrangements
listed above were all found after classical positional cloning strategies had identified them as PD genes and it was during the genetic characterisation of these genes that the rearrangements were demonstrated. Recent advances in genetic technologies allows for a rapid, robust genome wide search for CNVs. We plan to screen our series of patients for CNVs. In essence we will look in our recessive families for CNV, with particular emphasis on homozygous rearrangements. This work complements the objectives of subproject 2. We are also aware that single heterozygous rearrangements can cause autosomal dominant disease (eg a-syn). Therefore, in parallel with subproject 1 we will interrogate our AD PD families. Finally the role of ‘common’ CNVs has not been assessed in PD and we will adopt a genome wide search in 400 cases of sporadic pathologically proven PD.

Technical Summary

One of the major initial impacts of the human genome project was how little we understood about genomic diversity. Over the past 2-3 years it has become clear that there is tremendous variation in the numbers of copies of a large proportion of the human genome. There are some striking examples of copy numbers leading to human disease. The best characterised in neurological disease is the rearrangements around PMP22 giving rise to CMT1a and hereditary liability to pressure palsies. In Parkinson’s disease, of the currently identified genes,
rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-synuclein duplication or triplication is the commonest mutational mechanism. Copy number variation (CNVs) can be considered in 2 broad ways. First there are rare occurrences (as above) where the duplication or deletion of genomic region may lead to a highly penetrant ‘mendelian’ form of disease. In the second, there is the potential role of ‘common’ rearrangements in susceptibility to disease. In the case of PD the rearrangements
listed above were all found after classical positional cloning strategies had identified them as PD genes and it was during the genetic characterisation of these genes that the rearrangements were demonstrated. Recent advances in genetic technologies allows for a rapid, robust genome wide search for CNVs. We plan to screen our series of patients for CNVs. In essence we will look in our recessive families for CNV, with particular emphasis on homozygous rearrangements. This work complements the objectives of subproject 2. We are also aware that single heterozygous rearrangements can cause autosomal dominant disease (eg a-syn). Therefore, in parallel with subproject 1 we will interrogate our AD PD families. Finally the role of ‘common’ CNVs has not been assessed in PD and we will adopt a genome wide search in 400 cases of sporadic pathologically proven PD.

Publications

10 25 50
 
Description 2011 - MRC - Clinical Research Fellowship - amcneill
Amount £129,110 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2011 
End 07/2013
 
Description 2011 - NIHR - Equipment Grant - nwood
Amount £339,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 07/2011 
End 06/2012
 
Description 2011 - PUK - Filling the genetic gaps in Parkinson's - nwood
Amount £315,000 (GBP)
Funding ID G-1107 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2011 
End 11/2013
 
Description 2011 - WT - Equipment Grant - nwood
Amount £661,636 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2015
 
Title Copy number variation database 
Description Database of patients with copy number variation 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact Not yet 
 
Description International Parkinson's disease consortium 
Organisation Eberhard Karls University of Tubingen
Department Neurogenetics
Country Germany 
Sector Academic/University 
PI Contribution Principal UK contributor
Collaborator Contribution Building international consortium
Impact Publication in Nature genetics and Hum Mol genetics and a further recent submission
Start Year 2009
 
Description International Parkinson's disease consortium 
Organisation National Institute on Aging
Country United States 
Sector Public 
PI Contribution Principal UK contributor
Collaborator Contribution Building international consortium
Impact Publication in Nature genetics and Hum Mol genetics and a further recent submission
Start Year 2009
 
Description protein phosphorylation in PD 
Organisation University of Dundee
Department MRC Protein Phosphorylation and Ubiquitylation Unit
Country United Kingdom 
Sector Public 
PI Contribution Integrated biochemical approach to evaluating kinases involved in parkinsons pathophysiology
Impact Recent successful strategic award- Wellcome trust/MRC- neurodegenerative diseases
Start Year 2008
 
Description Neuromedia Corner 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviewed for a webcast explaining the recent advances in the genetics of Parkinson's Disease.


unknown
Year(s) Of Engagement Activity 2010
 
Description Parkinson's UK Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Details on the finding of 5 genes which are involved in Parkinson's disease

Picked up for UK press release
Year(s) Of Engagement Activity 2011
 
Description Parkinson's UK Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Information disseminated to the general public about how changes in PINK1 can lead to Parkinson's disease

Interest from PD society member visits to lab about the work that is being undertaken
Year(s) Of Engagement Activity 2010
 
Description Telegraph Article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release of the findings of genetic studies of Parkinson's disease

Increased interest from general public on PD genetic research
Year(s) Of Engagement Activity 2011