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Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach.

A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.

Pubmed ID: 18285836

Authors

  • Tischkowitz M
  • Hamel N
  • Carvalho MA
  • Birrane G
  • Soni A
  • van Beers EH
  • Joosse SA
  • Wong N
  • Novak D
  • Quenneville LA
  • Grist SA
  • kConFab
  • Nederlof PM
  • Goldgar DE
  • Tavtigian SV
  • Monteiro AN
  • Ladias JA
  • Foulkes WD

Journal

European journal of human genetics : EJHG

Publication Data

July 19, 2008

Associated Grants

  • Agency: NIA NIH HHS, Id: AG021964
  • Agency: NCI NIH HHS, Id: CA116167
  • Agency: NCI NIH HHS, Id: CA92309
  • Agency: NIDDK NIH HHS, Id: DK62162
  • Agency: NIA NIH HHS, Id: R01 AG021964-01
  • Agency: NCI NIH HHS, Id: R01 CA092309-02
  • Agency: NCI NIH HHS, Id: R01 CA116167
  • Agency: NCI NIH HHS, Id: R01 CA116167-05
  • Agency: NIDDK NIH HHS, Id: R01 DK062162-04

Mesh Terms

  • Adult
  • Amino Acid Substitution
  • BRCA1 Protein
  • Breast Neoplasms
  • Carrier Proteins
  • Chromosome Segregation
  • Conserved Sequence
  • DNA-Binding Proteins
  • Evolution, Molecular
  • Female
  • Humans
  • Likelihood Functions
  • Lysine
  • Male
  • Methionine
  • Middle Aged
  • Models, Molecular
  • Mutation, Missense
  • Nuclear Proteins
  • Nucleic Acid Hybridization
  • Pedigree
  • Phosphopeptides
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RNA Helicases