MURINE BRCA1 - SEQUENCE AND SIGNIFICANCE FOR HUMAN MISSENSE MUTATIONS

We have cloned and sequenced a mouse homologue of the human breast and ovarian cancer susceptibility gene, BRCA1. The predicted mouse Brca1 protein is composed of 1812 amino acids, The murine protein is 60% identical and 72% similar to the human BRCA1 protein, Two regions of high homology have been identified between the two proteins. First is the Cys3-His-Cys4 type zinc-finger domain that is identical between the two proteins, The second region is defined by 115 amino acids near the carboxy end of the Brca1 protein that is 83% identical to human BRCA1 sequence. Seven of eight amino acids involved in human missense mutations that are associated with the disease were found to be conserved between the two species, In contrast, most of the amino acids that are involved in polymorphic variations were not conserved. We therefore propose that the interspecies conservation of predicted amino acid sequences can be used as an additional criterion to determine the significance of human missense mutations.