Genetic association of DLG5 variant R30Q with IBD in a familial inflammatory bowel disease (IBD) registry

Abstract

The gene DLG5, a member of membrane associated guanylate kinase family, contains multiple functional domains such as leucine zipper, PDZ1, PDZ2, SH3, and GUK domains distributed over the entire gene. Any genetic variant that affects the structure of these domains may have impact on protein function in cell junction, maintenance of cell shape or clustering of channel proteins at the cell surface. A possible role of genetic variants of DLG5, such as R30Q, G1066G, e 26, and P1371Q, has been studied in IBD. However, for a better understanding of the contribution of these variants to IBD, more studies are needed. Using a central Pennsylvania familial IBD registry, we studied the genetic association of DLG5 with IBD. In addition to our DLG5 R30Q study reported elsewhere, we also analyzed four other single nucleotide polymorphisms (SNPs). SNPs E514Q, P979L, and P1371Q, are missense mutations that lead to protein amino acid sequence changes. SNP G1066G is at the second nucleotide of 5′ end of exon 16. Although it does not change the coding amino acid, it may have impact on DLG5 RNA splicing. A total of 244 individuals from 58 families, in which at least 2 individuals in each family were affected with IBD, were studied. 182 DNA samples from individuals without IBD served as controls. Genomic DNA isolated from lymphocyte and tissues was used for genotyping. The genotype analysis was carried out with PCR-based nature restriction fragment length polymorphism (RFLP) and converted RFLP methods. We found that: 1) for SNP G1066G, even the minor allele T is distributed to almost half of the population with no difference between diseased and nondiseased individuals. 2) Both E514Q and P979L are rare mutations. The frequency of mutated allele carrier is 4.5% for E514Q and 2.9% for P979L. The two mutations exist in both IBD patients and controls, their association with IBD is currently unclear due to the lack of statistic power. For SNP P1371Q, the frequency of mutation allele A is 8.2% in 244 individuals of the familial registry, and 11% in the 112 IBD affected individuals of the familial registry, and 9% in 169 sporadic IBD patients from our tissue bank, while only 6% in 182 normal controls. The results described above indicate that the DLG5 variant G1066G is probably not associated with IBD, whereas the variant P1371Q isfound at an increased incidence in both sporadic and familial form of IBD. The association of DLG variants, E514Q and P979L with IBD is currently unclear.