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Heredity in Parkinson's disease. From rare mutations to common genetic risk factors.

Puschmann, Andreas LU (2011) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2011:95.
Abstract
This study investigated genetic causes of Parkinson's disease (PD) and parkinsonism in southern Sweden.

The extensive Lister Family with parkinsonism caused by duplications and triplications of the gene for alpha-synuclein (SNCA) was studied. Clinical, genetic and genealogical data were compiled and evaluated. Thirty-five family members with parkinsonism were identified. They share a characteristic clinical subtype of parkinsonism with marked dysfunction of the autonomic nervous system, behavioral changes and cognitive decline. The clinical phenotype, heredity and genetic background of 132 probands from Southern Sweden with PD or parkinsonism was examined. The SNCA, LRRK2, EIF4G1, VPS35, PINK1, ATXN2 and ATXN3 genes were analyzed... (More)
This study investigated genetic causes of Parkinson's disease (PD) and parkinsonism in southern Sweden.

The extensive Lister Family with parkinsonism caused by duplications and triplications of the gene for alpha-synuclein (SNCA) was studied. Clinical, genetic and genealogical data were compiled and evaluated. Thirty-five family members with parkinsonism were identified. They share a characteristic clinical subtype of parkinsonism with marked dysfunction of the autonomic nervous system, behavioral changes and cognitive decline. The clinical phenotype, heredity and genetic background of 132 probands from Southern Sweden with PD or parkinsonism was examined. The SNCA, LRRK2, EIF4G1, VPS35, PINK1, ATXN2 and ATXN3 genes were analyzed in all probands; the PARKIN, PINK1 and DJ1 genes were tested in a subgroup of 23 patients with young onset or marked heredity. DNA from the brain tissue of 7 patients with parkinsonism was also analyzed. Common genetic risk factors in DNA samples collected within this study were analyzed in collaboration with other research groups.

Gene screening identified two rare causative mutations, SNCA A53T and LRRK2 N1437H. An additional patient was compound heterozygous for PARKIN R275W and R275Q mutations. Detailed information on their clinical picture is presented. We present the first neuropathological description of a patient with PD and LRRK2 N1437H mutation, showing

pronounced ubiquitin and moderate alpha-synuclein pathology. A heterozygous PINK1 G411S mutation was present in two PD patients but showed no clear co-segregation with the disease in their families. Screening of 1,107 patients and controls as well as meta-analysis of published reports from 7,800 individuals revealed that the PINK1 G411S mutation is a rare risk variant with a relatively large effect size (odds ratios 4.06-8.42). One multicenter study

confirmed that common variants in the SNCA and MAPT genes modify PD risk, and was large enough to refute gene-gene interaction between the MAPT and SNCA variants.

These results suggest that specific mutations in PD-genes cause characteristic disease subtypes. Despite extensive screening and a high proportion of familial cases, known pathogenic mutations could only explain a small proportion of parkinsonism in this cohort. This may indicate that mutations causing parkinsonism in the Scandinavian population remain to be discovered. Alternatively, familial clustering and sporadic occurrence of PD may be explained

by combinations of rare variants with relatively large effect size, such as PINK1 G411S. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • MD, MBChB, FRCP, PhD Nicholl, David J., University of Birmingham, U.K.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Parkinson's disease, parkinsonism, genetics, alpha-synuclein, SNCA duplicaion, SNCA triplication, LRRK2, PARKIN, PARK2, VPS35, EIF4G1, rare variants, digenic inheritance, heritability
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2011:95
pages
174 pages
publisher
Lund University
defense location
Segerfalksalen, Wallenberg Neurocentrum, Lund, Sweden
defense date
2011-10-14 14:00
ISSN
1652-8220
ISBN
978-91-86871-44-4
language
English
LU publication?
yes
id
6e50d0c5-ccdc-4816-9c4a-e3e5a23deaa5 (old id 2158813)
date added to LUP
2011-09-21 09:07:49
date last changed
2016-09-19 08:44:48
@phdthesis{6e50d0c5-ccdc-4816-9c4a-e3e5a23deaa5,
  abstract     = {This study investigated genetic causes of Parkinson's disease (PD) and parkinsonism in southern Sweden.<br/><br>
The extensive Lister Family with parkinsonism caused by duplications and triplications of the gene for alpha-synuclein (SNCA) was studied. Clinical, genetic and genealogical data were compiled and evaluated. Thirty-five family members with parkinsonism were identified. They share a characteristic clinical subtype of parkinsonism with marked dysfunction of the autonomic nervous system, behavioral changes and cognitive decline. The clinical phenotype, heredity and genetic background of 132 probands from Southern Sweden with PD or parkinsonism was examined. The SNCA, LRRK2, EIF4G1, VPS35, PINK1, ATXN2 and ATXN3 genes were analyzed in all probands; the PARKIN, PINK1 and DJ1 genes were tested in a subgroup of 23 patients with young onset or marked heredity. DNA from the brain tissue of 7 patients with parkinsonism was also analyzed. Common genetic risk factors in DNA samples collected within this study were analyzed in collaboration with other research groups.<br/><br>
Gene screening identified two rare causative mutations, SNCA A53T and LRRK2 N1437H. An additional patient was compound heterozygous for PARKIN R275W and R275Q mutations. Detailed information on their clinical picture is presented. We present the first neuropathological description of a patient with PD and LRRK2 N1437H mutation, showing<br/><br>
pronounced ubiquitin and moderate alpha-synuclein pathology. A heterozygous PINK1 G411S mutation was present in two PD patients but showed no clear co-segregation with the disease in their families. Screening of 1,107 patients and controls as well as meta-analysis of published reports from 7,800 individuals revealed that the PINK1 G411S mutation is a rare risk variant with a relatively large effect size (odds ratios 4.06-8.42). One multicenter study<br/><br>
confirmed that common variants in the SNCA and MAPT genes modify PD risk, and was large enough to refute gene-gene interaction between the MAPT and SNCA variants.<br/><br>
These results suggest that specific mutations in PD-genes cause characteristic disease subtypes. Despite extensive screening and a high proportion of familial cases, known pathogenic mutations could only explain a small proportion of parkinsonism in this cohort. This may indicate that mutations causing parkinsonism in the Scandinavian population remain to be discovered. Alternatively, familial clustering and sporadic occurrence of PD may be explained<br/><br>
by combinations of rare variants with relatively large effect size, such as PINK1 G411S.},
  author       = {Puschmann, Andreas},
  isbn         = {978-91-86871-44-4},
  issn         = {1652-8220},
  keyword      = {Parkinson's disease,parkinsonism,genetics,alpha-synuclein,SNCA duplicaion,SNCA triplication,LRRK2,PARKIN,PARK2,VPS35,EIF4G1,rare variants,digenic inheritance,heritability},
  language     = {eng},
  pages        = {174},
  publisher    = {Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Heredity in Parkinson's disease. From rare mutations to common genetic risk factors.},
  volume       = {2011:95},
  year         = {2011},
}