TP73allelic expression in human brain and allele frequencies in Alzheimer's disease

Abstract

BackgroundThe 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.MethodsWe 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.ResultsUsing 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.ConclusionsThere 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.

p73 G4C14-to-A4T14 Polymorphism and Risk of Lung Cancer

“…p73 gene structure and the positions of all 19 known single nucleotide polymorphisms (adapted from ref. 5,19,20). One, 2, 3, 9, 12, 13, 16, and 17 are within introns and located Ն16 bp from the splice sites, and these single nucleotide polymorphisms are thus unlikely to be deleterious mutations; 4,5,7,8,10,11,14,15,18, and 19 are single nucleotide polymorphisms within exons, which do not cause amino acid changes; and 6 is a SNP within promoter 3. allele.…”

“…The two common single nucleotide polymorphisms at positions 4 (G3 A) and 14 (C3 T) in the uncoding region of exon 2 of the p73 gene are in complete linkage disequilibrium with one another as one variant. The AT allele may affect p73 function, perhaps by altering the efficiency of translation initiation (5), whereas the P3 variant did not have a significant biological effect (20). Studies have investigated the role of the p73 G4C14-to-A4T14 polymorphism in risk of several types of cancer (21)(22)(23)(24) but only one examined non-small-cell lung cancer.…”

Combined Effects of the p53 and p73 Polymorphisms on Lung Cancer Risk

“…To date, there are at least 13 different polymorphisms identified in the human p53 gene (5, 6), of which 5 are found in exons and 8 in introns, and there are at least 19 polymorphisms in p73 (4,7,8), of which 10 are found in exons, 8 found in introns, and 1 found in the promoter region. At present, the functional effect for many of these polymorphisms is not known.…”

Concordance of functional in vitro data and epidemiological associations in complex disease genetics

“…Of the 36 evaluated bi-allelic polymorphisms 16 -51 (Table 1), 28 were located in the 5=-flanking region, 5 were exonic, 2 were intronic, and 1 lay in the 3=-untranslated region. A wide variety of disease phenotypes were probed.…”