Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1

Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1

The identification of founder mutations in cancer predisposing genes is important to improve risk assessment in geographically defined populations, since it may provide specific targets resulting in cost-effective genetic testing. Here, we report the characterization of the BRCA1 c.190T>C (p.Cys6...

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Main Authors: Caleca, Laura, Putignano, Anna Laura, Colombo, Mara, Congregati, Caterina, Sarkar, Mohosin, Magliery, Thomas J., Ripamonti, Carla B., Foglia, Claudia, Peissel, Bernard, Zaffaroni, Daniela, Manoukian, Siranoush, Tondini, Carlo, Barile, Monica, Pensotti, Valeria, Bernard, Loris, Papi, Laura, Radice, Paolo
Format: Online
Language:English
Published: Public Library of Science 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916327/
id pubmed-3916327
recordtype oai_dc
spelling pubmed-39163272014-02-10 Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1 Caleca, Laura Putignano, Anna Laura Colombo, Mara Congregati, Caterina Sarkar, Mohosin Magliery, Thomas J. Ripamonti, Carla B. Foglia, Claudia Peissel, Bernard Zaffaroni, Daniela Manoukian, Siranoush Tondini, Carlo Barile, Monica Pensotti, Valeria Bernard, Loris Papi, Laura Radice, Paolo Research Article The identification of founder mutations in cancer predisposing genes is important to improve risk assessment in geographically defined populations, since it may provide specific targets resulting in cost-effective genetic testing. Here, we report the characterization of the BRCA1 c.190T>C (p.Cys64Arg) mutation, mapped to the RING-finger domain coding region, that we detected in 43 hereditary breast/ovarian cancer (HBOC) families, for the large part originating from the province of Bergamo (Northern Italy). Haplotype analysis was performed in 21 families, and led to the identification of a shared haplotype extending over three BRCA1-associated marker loci (0.4 cM). Using the DMLE+2.2 software program and regional population demographic data, we were able to estimate the age of the mutation to vary between 3,100 and 3,350 years old. Functional characterization of the mutation was carried out at both transcript and protein level. Reverse transcriptase-PCR analysis on lymphoblastoid cells revealed expression of full length mRNA from the mutant allele. A green fluorescent protein (GFP)-fragment reassembly assay showed that the p.Cys64Arg substitution prevents the binding of the BRCA1 protein to the interacting protein BARD1, in a similar way as proven deleterious mutations in the RING-domain. Overall, 55 of 83 (66%) female mutation carriers had a diagnosis of breast and/or ovarian cancer. Our observations indicate that the BRCA1 c.190T>C is a pathogenic founder mutation present in the Italian population. Further analyses will evaluate whether screening for this mutation can be suggested as an effective strategy for the rapid identification of at-risk individuals in the Bergamo area. Public Library of Science 2014-02-06 /pmc/articles/PMC3916327/ /pubmed/24516540 http://dx.doi.org/10.1371/journal.pone.0086924 Text en © 2014 Caleca et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Caleca, Laura
Putignano, Anna Laura
Colombo, Mara
Congregati, Caterina
Sarkar, Mohosin
Magliery, Thomas J.
Ripamonti, Carla B.
Foglia, Claudia
Peissel, Bernard
Zaffaroni, Daniela
Manoukian, Siranoush
Tondini, Carlo
Barile, Monica
Pensotti, Valeria
Bernard, Loris
Papi, Laura
Radice, Paolo
spellingShingle Caleca, Laura
Putignano, Anna Laura
Colombo, Mara
Congregati, Caterina
Sarkar, Mohosin
Magliery, Thomas J.
Ripamonti, Carla B.
Foglia, Claudia
Peissel, Bernard
Zaffaroni, Daniela
Manoukian, Siranoush
Tondini, Carlo
Barile, Monica
Pensotti, Valeria
Bernard, Loris
Papi, Laura
Radice, Paolo
Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1
author_facet Caleca, Laura
Putignano, Anna Laura
Colombo, Mara
Congregati, Caterina
Sarkar, Mohosin
Magliery, Thomas J.
Ripamonti, Carla B.
Foglia, Claudia
Peissel, Bernard
Zaffaroni, Daniela
Manoukian, Siranoush
Tondini, Carlo
Barile, Monica
Pensotti, Valeria
Bernard, Loris
Papi, Laura
Radice, Paolo
author_sort Caleca, Laura
title Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1
title_short Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1
title_full Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1
title_fullStr Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1
title_full_unstemmed Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1
title_sort characterization of an italian founder mutation in the ring-finger domain of brca1
description The identification of founder mutations in cancer predisposing genes is important to improve risk assessment in geographically defined populations, since it may provide specific targets resulting in cost-effective genetic testing. Here, we report the characterization of the BRCA1 c.190T>C (p.Cys64Arg) mutation, mapped to the RING-finger domain coding region, that we detected in 43 hereditary breast/ovarian cancer (HBOC) families, for the large part originating from the province of Bergamo (Northern Italy). Haplotype analysis was performed in 21 families, and led to the identification of a shared haplotype extending over three BRCA1-associated marker loci (0.4 cM). Using the DMLE+2.2 software program and regional population demographic data, we were able to estimate the age of the mutation to vary between 3,100 and 3,350 years old. Functional characterization of the mutation was carried out at both transcript and protein level. Reverse transcriptase-PCR analysis on lymphoblastoid cells revealed expression of full length mRNA from the mutant allele. A green fluorescent protein (GFP)-fragment reassembly assay showed that the p.Cys64Arg substitution prevents the binding of the BRCA1 protein to the interacting protein BARD1, in a similar way as proven deleterious mutations in the RING-domain. Overall, 55 of 83 (66%) female mutation carriers had a diagnosis of breast and/or ovarian cancer. Our observations indicate that the BRCA1 c.190T>C is a pathogenic founder mutation present in the Italian population. Further analyses will evaluate whether screening for this mutation can be suggested as an effective strategy for the rapid identification of at-risk individuals in the Bergamo area.
publisher Public Library of Science
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916327/
_version_ 1612055840942981120

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