Background: Inflammatory bowel diseases (IBDs; ulcerative colitis, UC, and Crohn's disease, CD) show familial clustering suggestive of a genetic background. A linkage susceptibility region for these diseases (IBD9) lies on chromosome 3p and includes the DNA mismatch repair gene MLH1. Loss of MLH1 confers the characteristic microsatellite instability (MSI) phenotype which is also frequently found in the mucosa of IBD patients. A common germline alteration of MLH1 (655A>G) results in the amino acid exchange MLH1 I219V. Conflicting data exist on its effect on the function of the protein and it has recently been reported to cosegregate with refractory UC, suggesting that this alteration may impair mismatch repair activity and thereby contribute to certain forms of UC.
Methods: We analyzed the MLH1 I219V alteration using in silico and biochemical analyses and assessed its appearance in 67 well-classified UC patients in comparison to 40 healthy individuals.
Results: The analyses showed that I219 is a conserved, buried hydrophobic residue, and that I219V is unlikely to abolish MLH1 function but may modulate it. Quantitative biochemical evaluation showed identical stability and activity of the protein. Furthermore, the alteration occurred equally frequently in analyzed patients and healthy volunteers.
Conclusions: The MLH1 I219V alteration does not directly contribute to the etiology of UC through an impairment of mismatch repair. A putative linkage disequilibrium of MLH1 I219V with the causative gene(s) of the IBD9 locus is rather distant.