TP73 allelic expression in human brain and allele frequencies in Alzheimer's disease.
BACKGROUND
The p73 protein, a paralogue of the p53 tumor suppressor, is essential for normal development and survival of neurons. TP73 is therefore of interest as a candidate gene for Alzheimer's disease (AD) susceptibility. TP73 mRNA is transcribed from three promoters, termed P1-P3, and there is evidence for an additional complexity in its regulation, namely, a variable allelic expression bias in some human tissues.


METHODS
We utilized RT-PCR/RFLP and direct cDNA sequencing to measure allele-specific expression of TP73 mRNA, SNP genotyping to assess genetic associations with AD, and promoter-reporter assays to assess allele-specific TP73 promoter activity.


RESULTS
Using a coding-neutral BanI polymorphism in TP73 exon 5 as an allelic marker, we found a pronounced allelic expression bias in one adult brain hippocampus, while 3 other brains (two adult; one fetal) showed approximately equal expression from both alleles. In a tri-ethnic elderly population of African-Americans, Caribbean Hispanics and Caucasians, a G/A single nucleotide polymorphism (SNP) at -386 in the TP73 P3 promoter was weakly but significantly associated with AD (crude O.R. for AD given any -386G allele 1.7; C.I. 1.2-2.5; after adjusting for age and education O.R. 1.5; C.I. 1.1-2.3, N= 1191). The frequency of the -386G allele varied by ethnicity and was highest in African-Americans and lowest in Caucasians. No significant differences in basal P3 promoter activity were detected comparing -386G vs. -386A promoter-luciferase constructs in human SK-NSH-N neuroblastoma cells.


CONCLUSIONS
There is a reproducible allelic expression bias in mRNA expression from the TP73 gene in some, though not all, adult human brains, and inter-individual variation in regulatory sequences of the TP73 locus may affect susceptibility to AD. However, additional studies will be necessary to exclude genetic admixture as an alternative explanation for the observed associations.
Li
Quanyi
Q
Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University, New York, NY 10032, USA. ql2106@columbia.edu
Athan
Eleni S
ES
Wei
Michelle
M
Yuan
Eric
E
Rice
Samuel L
SL
Vonsattel
Jean-Paul
JP
Mayeux
Richard P
RP
Tycko
Benjamin
B
D000368:Aged; D000544:Alzheimer Disease / Q000208:ethnology / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D005787:Gene Frequency; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D001057:Apolipoproteins E; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D004247:DNA; D008156:Luciferases