IDENTIFICATION OF GENETIC MUTATIONS IN JAPANESE PATIENTS WITH FRUCTOSE-1,6-BISPHOSPHATASE DEFICIENCY

Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recess ive inherited disorder and may cause sudden unexpected infant-death. W e reported the first case of molecular diagnosis of FBPase deficiency, using cultured monocytes as a source for FBPase mRNA. In the present study, we confirmed the presence of the same genetic mutation in this patient by amplifying genomic DNA. Molecular analysis was also perform ed to diagnose another 12 Japanese patients with FBPase deficiency. Fo ur mutations responsible for FBPase deficiency were identified in 10 p atients from 8 unrelated families among a total of 13 patients from 11 unrelated families; no mutation was found in the remaining 3 patients from 3 unrelated families. The identified mutations included the muta tion reported earlier, with an insertion of one G residue at base 961 in exon 7 (960/961insG) (10 alleles, including 2 alleles in the Japane se family from our previous report [46% of the 22 mutant alleles]), an d three novel mutations-a G-->A transition at base 490 in exon 4 (G164 S) (3 alleles [14%]), a C-->A transversion at base 530 in exon 4 (A177 D) (1 allele [4%]), and a G-->T transversion at base 88 in exon 1 (E30 X) (2 alleles [9%]). FBPase proteins with G164S or A177D mutations wer e enzymatically inactive when purified from E. coli,Another new mutati on, a T-->C transition at base 974 in exon 7 (V325A), was found in the same allele with the G164S mutation in one family (one allele) but wa s not responsible for FBPase deficiency. Our results indicate that the insertion of one G residue at base 961 was associated with a preferen tial disease-causing alternation in 13 Japanese patients. Our results also indicate accurate carrier detection in eight families (73%) of 11 Japanese patients with FBPase deficiency, in whom mutations in both a lleles were identified.