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Common variations in the IL4R gene affect splicing and influence natural expression of the soluble isoform
Author(s) -
Bergin AnnMarie,
Balder Barbro,
Kishore Shivendra,
Swärd Kajsa,
HahnZoric Mirjana,
Löwhagen Olle,
Hanson Lars Å.,
Padyukov Leonid
Publication year - 2006
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20364
Subject(s) - biology , gene isoform , alternative splicing , affect (linguistics) , rna splicing , genetics , gene , gene expression , microbiology and biotechnology , rna , communication , sociology
Abstract We previously found the soluble interleukin 4 receptor (sIL4R) to be differently expressed in allergic asthma patients compared to healthy individuals. Here we present data demonstrating the involvement of the sequence variations, c.912–1003A>G, c.912–833T>C, c. 912–630A>G, and c.912–577A>G, in the expressional regulation of IL4R splice variants. By using an IL4R minigene construct, genomic DNA and mRNA from asthma patients and nonasthmatic individuals, we analyzed the function of four highly‐linked SNPs, flanking the alternatively‐spliced exon in the IL4R gene. Results from the minigene assay showed that the form containing the minor alleles significantly decreased the expression of the soluble IL4R (exon 8+) variant, a decrease that could only be seen in the major construct after increasing amounts of either the splicing factor SRp20, or YT521‐B. Analysis of mRNA expression in our human material confirmed the results, demonstrating lower expression of the sIL4R in patients and controls carrying the minor alleles. Together these results show sequence variations as a possible way of altering alternative splicing selection of IL4R in vivo. Hum Mutat 27(10), 990–998, 2006. © 2006 Wiley‐Liss, Inc.