Common variations in the IL4R gene affect splicing and influence natural expression of the soluble isoform.

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.

• Authors: Ann-Marie Bergin, Barbro Balder, Shivendra Kishore, Kajsa Swärd, Mirjana Hahn-Zoric, Olle Löwhagen, Lars A Hanson, Leonid Padyukov
• Journal: Human mutation (Hum Mutat) Vol. 27 Issue 10 Pg. 990-8 (Oct 2006) ISSN: 1098-1004 [Electronic] United States
• PMID: 16917945 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Protein Isoforms
• RNA Splicing Factors
• RNA, Messenger
• RNA-Binding Proteins
• Receptors, Interleukin-4
• SRSF3 protein, human
• YTHDC1 protein, human
• Serine-Arginine Splicing Factors

Topics

• Adolescent
• Adult
• Aged
• Asthma (genetics, metabolism)
• Base Sequence
• Binding Sites (genetics)
• Cell Line
• Female
• Gene Expression (genetics)
• Humans
• Immunoprecipitation (methods)
• Male
• Middle Aged
• Molecular Sequence Data
• Nerve Tissue Proteins (genetics, metabolism)
• Polymorphism, Single Nucleotide (genetics)
• Protein Binding
• Protein Isoforms (chemistry, genetics, metabolism)
• RNA Splicing (genetics)
• RNA Splicing Factors
• RNA, Messenger (genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Receptors, Interleukin-4 (chemistry, genetics, metabolism)
• Serine-Arginine Splicing Factors
• Solubility