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.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Institute Born-Bunge, Antwerpen, Belgium.
Veerle
V
Bogaerts
Sebastiaan
S
Engelborghs
Samir
S
Kumar-Singh
Dirk
D
Goossens
Barbara
B
Pickut
Julie
J
van der Zee
Kristel
K
Sleegers
Karin
K
Peeters
Jean-Jacques
JJ
Martin
Jurgen
J
Del-Favero
Thomas
T
Gasser
Dennis W
DW
Dickson
Zbigniew K
ZK
Wszolek
Peter P
PP
De Deyn
Jessie
J
Theuns
Christine
C
Van Broeckhoven
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