HEREDITARY TYROSINEMIA TYPE-1 - NOVEL MISSENSE, NONSENSE AND SPLICE CONSENSUS MUTATIONS IN THE HUMAN FUMARYLACETOACETATE HYDROLASE GENE - VARIABILITY OF THE GENOTYPE-PHENOTYPE RELATIONSHIP
Jkp. Vanamstel et al., HEREDITARY TYROSINEMIA TYPE-1 - NOVEL MISSENSE, NONSENSE AND SPLICE CONSENSUS MUTATIONS IN THE HUMAN FUMARYLACETOACETATE HYDROLASE GENE - VARIABILITY OF THE GENOTYPE-PHENOTYPE RELATIONSHIP, Human genetics, 97(1), 1996, pp. 51-59
The complete fumarylacetoacetate hydrolase (FAH) genotype of probands
of thirteen unrelated families with hereditary tyrosinemia type 1 (HT
1) was established. The screening was performed by analysis of exons 2
-14 of the FAH gene by using the polymerase chain reaction (PCR) and o
f the mRNA by reverse transcription/PCR. Nine different mutations were
identified, of which six are novel. Three mutations involve consensus
sequences for correct splicing, viz. IVS 6-1 (g-t), IVS 7-1 (g-a) and
IVS 12 + 5 (g-a). Two missense mutations (C193R and G369V) and three
nonsense mutations (R237X, E357X and E364X) were found. One silent mut
ation N232N was associated with the skipping of exon 8 from the FAH mR
NA. Analysis of the effect of the respective mutations on the FAH mRNA
showed a strong reduction of FAH mRNA levels in association with the
nonsense mutations, and normal levels with the missense mutations. The
splice consensus mutations give deletions of complete or small parts
of exon sequences from the FAH mRNA. Data suggest a founder effect for
several of the mutations, with a frequency for both the IVS 6-1 (g-t)
and IVS 12 + 5 (g-a) mutations of approximately 30% in the HT 1 proba
nds. No strict correlation between genotype and phenotype, i.e. the ac
ute, subacute or chronic form of HT 1, was evident.