title: Expression analysis of MLH3, MLH1, and MSH4 in maturation arrest.
abstract: The expression of DNA mismatch repair (DMMR) genes in patients with maturation arrest (MA) was analyzed. Samples were subjected to mutL homolog 3 (MLH3) mutation analysis by denaturing high-performance liquid chromatography/sequencing and quantification of MMR expression in testicular tissue by real-time polymerase chain reaction (PCR). Microsatellite instability assays were negative. Two missense and 1 intronic mutations were found. The missense mutation 2531C/T (P844 L), predicted to affect MLH3 function, was found in 3 MA cases in association with the intronic variant IVS9 + 66G/A. Relative messenger RNA (mRNA) quantification identified 2 patients who overexpressed MLH3, 1 of them also overexpressing mutL homolog 1 (MLH1). The latter also presented the 2531C/T-IVS9 + 66G/A mutation. In conclusion, we suggest that a predominance of MLH3 expression might favor the MLH1/MLH3 complex which then would compete with the MLH1/PMS2 complexes. This could convey disruption of the relative stoichiometry between MLH1/MLH3 and MLH1/PMS2 complexes, thus causing meiosis failure, as MLH1/PMS2 complexes are supposed to replace MLH1/MLH3 during diplonema.
authors.affiliation: Laboratory of Chromosome Instability and Dynamics, Institute for Molecular Cell Biology (IBMC), Rua do Campo Alegre, Porto, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferrás
authors.forename: Susana
authors.initials: S
authors.lastname: Fernandes
authors.forename: Joaquina
authors.initials: J
authors.lastname: Silva
authors.forename: Alberto
authors.initials: A
authors.lastname: Barros
authors.forename: Mário
authors.initials: M
authors.lastname: Sousa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D053713:Azoospermia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D041322:Chromosomes, Human, Y / Q000235:genetics; D004247:DNA / Q000097:blood; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008297:Male; D008540:Meiosis; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D013090:Spermatocytes / Q000378:metabolism / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C501486:MLH1 protein, human; C403623:MLH3 protein, human; C409221:MSH4 protein, human; D009687:Nuclear Proteins; D004247:DNA; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins