title: A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function.
abstract: OBJECTIVE
  BRCA1-interacting protein 1 (BRIP1; FANCJ/BACH1), which encodes a DNA helicase that interacts with BRCA1, has been suggested to be a low-penetrance breast cancer predisposing gene. We aimed to assess whether BRIP1 mutations contribute to breast cancer susceptibility in our population and, if so, to investigate the effect of such mutation(s) on BRIP1 function.
  
  
  METHODS
  A series of 49 breast/ovarian cancer families, devoid of a BRCA1/BRCA2 mutation, were screened for BRIP1 mutations. Functional analyses, including coimmunoprecipitation and stability assays, were employed to further characterize a previously unreported variant.
  
  
  RESULTS
  Five sequence alterations were identified, of which four had been already described. Herein, we report a novel BRIP1 germ-line mutation identified in a woman with early-onset breast cancer. The mutation consists of a 4-nucleotide deletion (c.2992-2995delAAGA) in BRIP1 exon 20 that causes a shift in the reading frame, disrupts the BRCA1-binding domain of BRIP1, and creates a premature stop codon. Functional analysis of the recombinant mutant protein in transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1. Loss of the wild-type BRIP1 allele with retention of the mutated one was observed in the patient's breast tumor tissue.
  
  
  CONCLUSIONS
  These results, by showing that the newly identified BRIP1 c.2992-2995delAAGA mutation is associated with instability and functional impairment of the encoded protein, provide further evidence of a breast cancer-related role for BRIP1.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Arcangela
authors.initials: A
authors.lastname: De Nicolo
authors.forename: Mariella
authors.initials: M
authors.lastname: Tancredi
authors.forename: Grazia
authors.initials: G
authors.lastname: Lombardi
authors.forename: Cristina Chantal
authors.initials: CC
authors.lastname: Flemma
authors.forename: Serena
authors.initials: S
authors.lastname: Barbuti
authors.forename: Claudio
authors.initials: C
authors.lastname: Di Cristofano
authors.forename: Bijan
authors.initials: B
authors.lastname: Sobhian
authors.forename: Generoso
authors.initials: G
authors.lastname: Bevilacqua
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.forename: Maria Adelaide
authors.initials: MA
authors.lastname: Caligo
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D010375:Pedigree; D020365:RNA Helicases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C000618935:BRIP1 protein, human; D020365:RNA Helicases