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 fumarylace‐toacetate 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 find 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.