title: Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1.
abstract: 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 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.
authors.affiliation: Section of Human Biochemical Genetics, Human Genetics Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Hahn
authors.forename: D
authors.initials: D
authors.lastname: Krasnewich
authors.forename: M
authors.initials: M
authors.lastname: Brantly
authors.forename: E A
authors.initials: EA
authors.lastname: Kvittingen
authors.forename: W A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D005091:Exons; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D012326:RNA Splicing / Q000235:genetics*; D014443:Tyrosine / Q000097:blood* / Q000235:genetics*
chemical_list: D014443:Tyrosine