Published online Dec 14, 2013. doi: 10.3748/wjg.v19.i46.8659
Revised: July 26, 2013
Accepted: August 17, 2013
Published online: December 14, 2013
Processing time: 224 Days and 4.8 Hours
AIM: To investigated the molecular cause of very early-onset ulcerative colitis (UC) in an 18-mo-old affected child.
METHODS: We analysed the interleukin-10 (IL10) receptor genes at the DNA and RNA level in the proband and his relatives. Beta catenin and tumor necrosis factor-α (TNFα) receptors were analysed in the proteins extracted from peripheral blood cells of the proband, his relatives and familial adenomatous polyposis (FAP) and PTEN hamartoma tumor syndrome (PHTS) patients. Samples were also collected from the proband’s inflamed colorectal mucosa and compared to healthy and tumour mucosa collected from a FAP patient and patients affected by sporadic colorectal cancer (CRC). Finally, we examined mesalazine and azathioprine effects on primary fibroblasts stabilised from UC and FAP patients.
RESULTS: Our patient was a compound heterozygote for the IL10RB E47K polymorphism, inherited from his father, and for a novel point mutation within the IL10RA promoter (the -413G->T), inherited from his mother. Beta catenin and tumour necrosis factor α receptors-I (TNFRI) protein were both over-expressed in peripheral blood cells of the proband’s relatives more than the proband. However, TNFRII was over-expressed only in the proband. Finally, both TNFα-receptors were shown to be under-expressed in the inflamed colon mucosa and colorectal cancer tissue compared to healthy colon mucosa. Consistent with this observation, mesalazine and azathioprine induced, in primary fibroblasts, IL10RB and TNFRII over-expression and TNFRI and TNFα under-expression. We suggest that β-catenin and TNFRI protein expression in peripheral blood cells could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC.
CONCLUSION: A synergistic effect of several variant alleles of the IL10 receptor genes, inherited in a Mendelian manner, is involved in UC onset in this young child.
Core tip: We identified a novel point mutation within the interleukin-10 (IL10) receptor genes promoter (the -413G->T), associated with mRNA under-expression. We propose that this mutation has a synergistic effect with other variant alleles of IL10 receptor genes in very-early ulcerative colitis (UC) onset in this young child. β-catenin and tumour necrosis factor α receptors-I (TNFRI) protein were both over-expressed in peripheral blood cells of proband relatives, whereas TNFRII was over-expressed only in the proband. We suggest that β-catenin and TNFRI protein expression could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC.