I219V polymorphism in hMLH1 gene in patients affected with ulcerative colitis.
BACKGROUND
hMLH1 gene, lying on chromosome 3p21-23, is a key factor of the mismatch repair (MMR) complex, which amends DNA replication errors. MMR alterations are involved in the development of both hereditary and sporadic forms of colorectal carcinoma related to ulcerative colitis (UC). I219V Polymorphism is located on exon 8 of hMLH1 and provides an aminoacidic substitution of isoleucine to valine, on the protein codon 219. This may affect the speed and fidelity of protein synthesis because of a tRNA paucity or changes in the mRNA secondary structure. Most of the hereditary nonpolyposis colon cancer-associated missense mutations of hMLH1 cause structural changes of the amino- or carboxy-terminal regions, involving the domains that interact with ATP and hPMS2.


OBJECTIVE
In this study, we analyzed the hMLH1 I219V polymorphism frequency in colectomized patients with UC. Venous blood from 100 ulcerative patients and 97 apparently healthy subjects has been collected. Out of 100 patients affected with UC, 75 noncolectomized showed an alternating course of disease, while 25 did not respond to the common drugs, and underwent colectomy. Genotyping was performed by polymerase chain reaction and following enzymatic digestion by BccI.


RESULTS
No significant differences were found between patients with UC and controls both for genotype and allele frequencies. However, our data show a significant association when colectomized and noncolectomized patients are compared. The frequencies of G homozygosity were 28% in colectomized and 10.7% in noncolectomized patients (p < 0.05, chi(2) = 4.4, Odds ratio = 3.3). The allele frequencies of allele A were 52% in colectomized and 68% in noncolectomized patients; while those of allele G were 48% and 32%, respectively.


CONCLUSIONS
I219V polymorphism in hMLH1 could influence the clinical course of the disease and lead to resistance to therapy.
Vietri
Maria Teresa
MT
Dipartimento di Patologia generale, Cattedra di Patologia clinica, Seconda Università degli studi Napoli, Naples, Italy.
Riegler
Gabriele
G
De Paola
Marialaura
M
Simeone
Serena
S
Boggia
Maria
M
Improta
Alessia
A
Parisi
Mariarita
M
Molinari
Anna Maria
AM
Cioffi
Michele
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D003082:Colectomy; D003093:Colitis, Ulcerative / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005843:Geography; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1