HETEROZYGOSITY FOR AN EXON-12 SPLICING MUTATION AND A W234G MISSENSE MUTATION IN AN AMERICAN CHILD WITH CHRONIC TYROSINEMIA TYPE-1

Hereditary tyrosinemia type 1, an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH), manifests in either an acute or a chronic form, We used reverse transcription and the polymerase chain reaction to amplify the FAH cDNA of a 12-year-old American boy with chronic tyrosinemia type 1. The patient is a compound heterozygote for mutations in the FAH gene. One allele contains a missense mutation in codon 234 changing a tryptophan to a glycine; this allele was of maternal origin. Mutagenesis and transfection into COS cells demonstrated that the W234G mutation abolishes FAH activity. The patient's paternally derived allele is a splicing mutation in the + 5 position of intron 12, causing either insertion of a 105 bp fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13. The chronic phenotype of tyrosinemia type 1 in this patient may be due to some residual, correct splicing by the allele with the splicing mutation. (C) 1995 Wiley-Liss, Inc.