SINGLE MUTATION OF THE FUMARYLACETOACETATE HYDROLASE GENE IN FRENCH-CANADIANS WITH HEREDITARY TYROSINEMIA TYPE-I

Background. Hereditary tyrosinemia type I is an autosomal recessive in born error of metabolism caused by a deficiency of the enzyme fumaryla cetoacetate hydrolase. The disorder clusters in the Saguenay-Lac-St.-J ean area of Quebec. In this region, 1 of 1846 newborns is affected and 1 of every 22 persons is thought to be a carrier. Recently, we identi fied a splice mutation and two nonsense mutations in the fumarylacetoa cetate hydrolase gene in two patients from Quebec with tyrosinemia typ e I. Methods. We used allele-specific-oligonucleotide hybridization to examine the frequency of these three candidate mutations in patients with tyrosinemia type I and in the population of Quebec. Results. The splice mutation was found in 100 percent of patients from the Saguenay -Lac-St.-Jean area and in 28 percent of patients from other regions of the world. Of 25 patients from the Saguenay-Lac-St.-Jean region, 20 ( 80 percent) were homozygous for this mutation, a guanine-to-adenine ch ange in the splice-donor sequence in intron 12 of the gene, indicating that it causes most cases of tyrosinemia type I in the region. The fr equency of carrier status, based on screening of blood spots from newb orns, was about 1 per 25 in the Saguenay-Lac-St.-Jean population and a bout 1 per 66 overall in Quebec. Conclusions. This study identified th e most prevalent mutation causing hereditary tyrosinemia in French Can ada; it also showed the feasibility of DNA-based testing for carriers in the population at risk.