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Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg)

Willems, Petra; Magri, V.; Čretnik, Maja; Fasano, Mauro; Jakubowska, Ania; Levanat, Sonja; Lubinski, J.; Marras, E.; Musani, Vesna; Thierens, Hubert; Vandersickel, Veerle; Perletti, Gianpaolo; Vral, Anne (2009) Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg). International Journal of Oncology, 34 (4). pp. 1005-1015. ISSN 1019-6439

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In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms.

Item Type: Article
Uncontrolled Keywords: BRCA1; mutation; splicing
Subjects: BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions: Division of Molecular Medicine
Project titleProject leaderProject codeProject type
Signal transduction in tumors: Hh-Gli interactions and therapeutic potential (Prijenos signala u tumorima: Hh-Gli put, interakcije i potencijalne terapije)-Sonja Levanat098-0982464-2461MZOS
Depositing User: Maja Sabol
Date Deposited: 27 Nov 2015 12:28
DOI: 10.3892/ijo_00000226

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