TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.
Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3'-untranslated region (3'-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3'-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy.
Gitcho
Michael A
MA
Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Bigio
Eileen H
EH
Mishra
Manjari
M
Johnson
Nancy
N
Weintraub
Sandra
S
Mesulam
Marsel
M
Rademakers
Rosa
R
Chakraverty
Sumi
S
Cruchaga
Carlos
C
Morris
John C
JC
Goate
Alison M
AM
Cairns
Nigel J
NJ
D020413:3' Untranslated Regions / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001344:Autopsy / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D012333:RNA, Messenger