Characterization of an Italian founder mutation in the RING-finger domain of BRCA1

Laura Caleca, Anna Laura Putignano, Mara Colombo, Caterina Congregati, Mohosin Sarkar, Thomas J. Magliery, Carla B. Ripamonti, Claudia Foglia, Bernard Peissel, Daniela Zaffaroni, Siranoush Manoukian, Carlo Tondini, Monica Barile, Valeria Pensotti, Loris Bernard, Laura Papi, Paolo Radice

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere86924
JournalPLoS One
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 6 2014

Fingerprint

RING Finger Domains
BRCA1 Protein
mutation
Mutation
RNA-Directed DNA Polymerase
Green Fluorescent Proteins
Risk assessment
Assays
Screening
Proteins
Substitution reactions
Genes
Messenger RNA
ovarian neoplasms
Testing
Ovarian Neoplasms
Haplotypes
Costs
haplotypes
Breast Neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 9, No. 2, e86924, 06.02.2014.

Research output: Contribution to journalArticle

Caleca, L, Putignano, AL, Colombo, M, Congregati, C, Sarkar, M, Magliery, TJ, Ripamonti, CB, Foglia, C, Peissel, B, Zaffaroni, D, Manoukian, S, Tondini, C, Barile, M, Pensotti, V, Bernard, L, Papi, L & Radice, P 2014, 'Characterization of an Italian founder mutation in the RING-finger domain of BRCA1', PLoS One, vol. 9, no. 2, e86924. https://doi.org/10.1371/journal.pone.0086924
Caleca L, Putignano AL, Colombo M, Congregati C, Sarkar M, Magliery TJ et al. Characterization of an Italian founder mutation in the RING-finger domain of BRCA1. PLoS One. 2014 Feb 6;9(2). e86924. https://doi.org/10.1371/journal.pone.0086924
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. In: PLoS One. 2014 ; Vol. 9, No. 2.
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AU - Tondini, Carlo

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