Submission Details

BRIP1 gene, the BRCA1-interacting helicase, has been associated with Fanconi anemia of complementation group J (FANCJ) (#609054). At least 27 variants have reported in unrelated families/groups. Here we record 5 individuals in 4 families (3 Innuit individuals and 2 Hispanic individuals) and 6 individuals in a group of 18 FA cases of unassigned FA complementation group from IFAR [Livran O et al., PubMed: 16116424]; 6 individuals from various backgrounds, many with reported consanguinity (Iran, Canada, UK and Kuwait) from EUFA [Levitus M et al., PMID: 16116423]. Most of these FA individuals either have homozygous or compound heterozygous mutations in BRIP1 gene. The most common one, 2533C>T (R798X), may be a hot spot or an ancient mutation. Immunoblotting showed no BRIP1 protein in lymphoblastoid cells line from individuals who were homozygous or heterozygous with respect to 2533C-T/R798X (R798X/8003A>T and R798X/Y800X) (Levran O et al., 2005.). Western blot using antibody against BRIP1 showed the absence of a full-length BRIP1 protein band in nuclear extracts from cell lines carrying truncating mutations, whereas an attenuated band was observed in the cell line from individual EUFA776 with two missense mutations (1941G>C/W647C and 2119C>T/R707C) (Levitus M et al,. 2005.). Purified recombinant A349P allele protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line. Experimental evidences are replicably showed its DNA repair function. Mutations in this gene abolish its DNA helicase activity in cellular levels and animal models.