Characterization of two novel FANCG mutations in Indian Fanconi anemia patients

- FANCG gene mutations are not reported systematically from Indian FA patients.
- C.1143 + 5 G > C mutation of intron9 causes exon9 skipping and can hamper TPR3 motif.
- C.883dupG mutation causes truncation before TPR3 motif and remainder C-terminus.
- Del-ins mutation c.1471_1473delAAAinsG hampers TPR6 and the remainder C-terminus.

FA is a rare recessive genetic disorder with autosomal or X-linked mode of inheritance and is associated with 19 different FA complementation groups. We have studied three patients clinically diagnosed as FA. All three patients showed a high frequency chromosomal breakage in MMC induced blood cultures and FANCD2 non-monoubiquitination by western blotting. The molecular analysis using direct sequencing revealed two novel mutations in FANCG; 2 novel mutations c.1143 + 5G > C and c.883dupG, and a reported mutation c.1471_1473delAAAinsG. We have for the first time modeled FANCG protein with fold based template search using pGenthreader which revealed sequence fold identical to super helical TPR domain of O linked GLCNAC transferase and have studied the impact of mutations on the function and structure of FANCG. All three mutations are potential pathogenic molecular changes which can affect FANCG interactions required for FA pathway, homologous recombination repairs and unhooking step of the ICL repair process.