A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I.
BACKGROUND
Hereditary tyrosinemia type I is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme fumarylacetoacetate hydrolase. The disorder clusters in the Saguenay-Lac-St.-Jean 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 identified a splice mutation and two nonsense mutations in the fumarylacetoacetate hydrolase gene in two patients from Quebec with tyrosinemia type 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 change 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 frequency of carrier status, based on screening of blood spots from newborns, was about 1 per 25 in the Saguenay-Lac-St.-Jean population and about 1 per 66 overall in Quebec.


CONCLUSIONS
This study identified the most prevalent mutation causing hereditary tyrosinemia in French Canada; it also showed the feasibility of DNA-based testing for carriers in the population at risk.
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland 97201-3098.
M
M
Grompe
M
M
St-Louis
S I
SI
Demers
M
M
al-Dhalimy
B
B
Leclerc
R M
RM
Tanguay
D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005240:Feasibility Studies; D006579:Heterozygote; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011792:Quebec; D014443:Tyrosine / Q000097:blood* / Q000235:genetics
D017931:DNA Primers; D014443:Tyrosine; D006867:Hydrolases; C020156:fumarylacetoacetase