A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder.
Dementia with Lewy bodies (DLB) represents the second most frequent type of neurodegenerative dementia in the elderly. Although most patients have sporadic DLB, a limited number of DLB families have been described, suggesting that genetic factors may contribute to DLB pathogenesis. Here, we describe a three-generation Belgian family with prominent dementia and parkinsonism, consistent with a diagnosis of DLB, that was autopsy confirmed for the index patient. In a genome-wide scan and subsequent finemapping of candidate loci we obtained significant linkage to 2q35-q36 (Z = 3.01 at D2S1242). Segregation analysis defined a candidate region of 9.2 Mb between D2S433 and chr2q36.3-8, adjacent to the previously reported PARK11 locus. In addition, haplotype sharing studies in another DLB family of close geographical origin with similar clinical and neuropathological features highlighted the specificity of a 2q35-q36 haplotype harbouring a pathogenic mutation that causes DLB in the Belgian family. So far, extensive sequence analysis of five candidate genes within the 2q35-q36 region has not revealed a disease-causing mutation. Together, our data re-emphasize the genetic heterogeneity of DLB, and strongly support the existence of a gene for familial DLB on 2q35-q36. Once identified this will be the first novel causal gene for DLB and can be expected to open new avenues for biological studies of the disease process.
Bogaerts
Veerle
V
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Institute Born-Bunge, Antwerpen, Belgium.
Engelborghs
Sebastiaan
S
Kumar-Singh
Samir
S
Goossens
Dirk
D
Pickut
Barbara
B
van der Zee
Julie
J
Sleegers
Kristel
K
Peeters
Karin
K
Martin
Jean-Jacques
JJ
Del-Favero
Jurgen
J
Gasser
Thomas
T
Dickson
Dennis W
DW
Wszolek
Zbigniew K
ZK
De Deyn
Peter P
PP
Theuns
Jessie
J
Van Broeckhoven
Christine
C
D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics* / Q000473:pathology; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology; D010375:Pedigree