Novel mutations in patients with fructose-1,6-bisphosphatase deficiency

Fructose-1,6-bisyhosphatase (FBPase) deficiency is an autosomal recessive disorder of gluconeogenesis. Mutations have recently been identified in Japanese patients but none has been reported in patients of other ethnic backgrounds. We have undertaken sequence analysis on genomic DNA isolated from leukocytes of four patients with FBPase deficiency. Homozygous mutations were found in all four cases. One patient was homozygous for the common mutation identified in Japanese patients (960-961insG in exon 7). The other three patients were all homozygous for novel mutations (35delA in exon 1, 778G --> A in exon 6 and 966delC in exon 7). Normal and mutant FBPases were expressed in prokaryotic (E. coli TG2) and eukaryotic (COS1) cells. In cell-free extracts the mutant proteins were enzymatically inactive, indicating that the mutations are responsible for the disease. In one affected family, molecular genetic analysis allowed the diagnosis to be excluded promptly in a newborn child 3 days after birth.