Document Detail


A compensatory effect upon splicing results in normal function of the CYP2A6*14 allele.
MedLine Citation:
PMID:  23292114     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A synonymous variant in the first exon of CYP2A6, rs1137115 (51G>A), defines the common reference allele CYP2A6*1A, and is associated with lower mRNA expression and slower in-vivo nicotine metabolism. Another common allele, CYP2A6*14, differs from CYP2A6*1A by a single variant, rs28399435 (86G>A, S29N). However, CYP2A6*14 shows in-vivo activity comparable with that of full-function alleles, and significantly higher than CYP2A6*1A. rs1137115A is predicted to create an exonic splicing suppressor site overlapping an exonic splicing enhancer (ESE) site in the first exon of CYP2A6, whereas rs28399435A is predicted to strengthen another adjacent ESE, potentially compensating for rs1137115A. Using an allelic expression assay to assess cDNAs produced from rs1137115 heterozygous liver biopsy samples, lower expression of the CYP2A6*1A allele is confirmed while CYP2A6*14 expression is found to be indistinguishable from that of rs1137115G alleles. Quantitative PCR assays to determine the relative abundance of spliced and unspliced or partially spliced CYP2A6 mRNAs in liver biopsy samples show that *1A/*1A homozygotes have a significantly lower ratio, due to both a reduction in spliced forms and an increase in unspliced or partially spliced CYP2A6. These results show the importance of common genetic variants that effect exonic splicing suppressor and ESEs to explain human variation regarding clinically-relevant phenotypes.
Authors:
A Joseph Bloom; Oscar Harari; Maribel Martinez; Xiaochun Zhang; Sandra A McDonald; Sharon E Murphy; Alison Goate
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  23     ISSN:  1744-6880     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-01-28     Completed Date:  2013-07-05     Revised Date:  2014-04-28    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  107-16     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alleles*
Aryl Hydrocarbon Hydroxylases / genetics*
Base Sequence
DNA Primers
Exons
Humans
Liver / enzymology
RNA Splicing*
Real-Time Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
1RR024992/RR/NCRR NIH HHS; 5T32MH014677-33/MH/NIMH NIH HHS; AA015572/AA/NIAAA NIH HHS; CA089392/CA/NCI NIH HHS; CA77598/CA/NCI NIH HHS; CA91842/CA/NCI NIH HHS; DA021237/DA/NIDA NIH HHS; K01 AA015572/AA/NIAAA NIH HHS; K02 DA021237/DA/NIDA NIH HHS; KL2 RR024994/RR/NCRR NIH HHS; P01 CA089392/CA/NCI NIH HHS; R25 DA027995/DA/NIDA NIH HHS; T32 MH014677/MH/NIMH NIH HHS; UL1 RR024992/RR/NCRR NIH HHS; UL1 RR024992/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; EC 1.14.13.-/coumarin 7-hydroxylase; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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