TAU as a susceptibility gene for amyotropic lateral sclerosis-parkinsonism dementia complex of Guam.
BACKGROUND
A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G.


METHODS
TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU.


RESULTS
Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G.


CONCLUSIONS
The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.
Poorkaj
P
P
Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA.
Tsuang
D
D
Wijsman
E
E
Steinbart
E
E
Garruto
R M
RM
Craig
U K
UK
Chapman
N H
NH
Anderson
L
L
Bird
T D
TD
Plato
C C
CC
Perl
D P
DP
Weiderholt
W
W
Galasko
D
D
Schellenberg
G D
GD
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D003704:Dementia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006141:Guam; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D016875:tau Proteins / Q000235:genetics*
D016875:tau Proteins