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TAU as a Susceptibility Gene for Amyotropic Lateral Sclerosis–Parkinsonism Dementia Complex of Guam
Parvoneh Poorkaj, PhD;
Debby Tsuang, MD;
Ellen Wijsman, PhD;
Ellen Steinbart, MA;
Ralph M. Garruto, PhD;
Ulla-Katrina Craig, PhD;
Nicola H. Chapman, PhD;
Leojean Anderson, BS;
Thomas D. Bird, MD;
Chris C. Plato, PhD;
Daniel P. Perl, MD;
Wigbert Weiderholt, MD;
Douglas Galasko, MD;
Gerard D. Schellenberg, PhD
Arch Neurol. 2001;58:1871-1878.
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.
From the Geriatric Research Education Clinical Center (Drs Poorkaj,
Bird, and Schellenberg and Mss Steinbart and Anderson) and Mental
Illness Research Education Clinical Center (Dr Tsuang), Veterans
Affairs Puget Sound Health Care System, Seattle Division, Seattle,
Wash; Division of Gerontology and Geriatric Medicine (Dr Poorkaj) and
Departments of Psychiatry and Behavioral Sciences (Dr Tsuang),
Biostatistics (Drs Wijsman and Chapman), Medicine (Division of Medical
Genetics) (Drs Wijsman and Bird), Neurology (Drs Bird and
Schellenberg), and Pharmacology (Dr Schellenberg), University of
Washington, Seattle; Departments of Anthropology and Biological
Sciences, Binghamton University, State University of New York,
Binghamton, NY (Dr Garruto); National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, Md (Dr
Garruto); Department of Public Health, University of Guam, Mangilao (Dr
Craig); Neurosciences Department, University of San Diego, San Diego,
Calif (Drs Plato, Weiderholt, and Galasko); and Departments of
Pathology and Psychology, Mount Sinai School of Medicine, New York, NY
(Dr Perl)
Corresponding author and reprints: Gerard D. Schellenberg, PhD,
GRECC 182-B, Veterans Affairs Puget Sound Health Care System, 1660
S Columbian Way, Seattle, WA 98108 (e-mail: zachdad{at}u.washington.edu).
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