Novel mutations of the FANCG gene causing alternative splicing in JapaneseFanconi anemia

Fanconi anemia (FA), an autosomal recessive disorder characterized by a pro gressive pancytopenia associated with congenital anomalies and high predisp osition to malignancies, is a genetically and clinically heterogeneous dise ase. At least eight complementation groups (FA-A to FA-H) have been identif ied. Previously, we studied mutations of the FANCA gene, responsible for FA -A, and found pathogenic mutations in 12 of 15 unclassified Japanese FA pat ients. Here, we further studied an additional 5 FA patients for sequence al terations of the FANCA gene and found pathogenic mutations in 2 of them. We further analyzed mutations of the FANCC and FANCG genes: responsible for F A-C and FA-G, respectively, in the remaining 6 FA patients. Although there was no alterations in the FANCC gene in these 6 patients, two novel mutatio ns of the FANCG gene, causing aberrant RNA splicing, were detected in 2 FA patients. One was a base substitution from G to C of the invariant GT dinuc leotides at the splice donor site of intron 3, resulting in the skipping of exon 3, as well as the skipping of exons 3 and 4. The other was a base sub stitution from C to T in exon 8, creating a nonsense codon (Q356X). This mu tation resulted in the exclusion of a sequence of 18 nucleotides containing the mutation from the mRNA, without affecting the splicing potential of ei ther the authentic or the cryptic splice donor site. Collectively, 14 of th e 20 unclassified Japanese FA patients belong to the FA-A group, 2 belong t o the FA-G group, and none belongs to the FA-C group.