Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship

Abstract

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 of 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 mutation N232N was associated with the skipping of exon 8 from the FAH mRNA. 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 probands. No strict correlation between genotype and phenotype, i.e. the acute, subacute or chronic form of HT 1, was evident.

Identification of a Rare Mutation Causing Hereditary Tyrosinemia Type 1 in an Iranian Child Compound with Dextrocardia Phenotype

“…The Iranian child with a compound clinical phenotype of dextrocardia and HT1, is a heterozygous with this mutation. Therefore, he presented with a chronic progression and slightly increased succinylacetone in the blood, compared to the acute form of HT1 with R237X homozygous reported previously [3,8]. The result of this study has application in patient screening and genetic counseling.…”

“…The mutation of R237X was first reported in a Turkish proband with HT1. This proband carried the homozygous R237X mutation [8]. Another nine forms of HT1 patient coming from different families in Saudi Arabia were also detected with the homozygous R237X mutations [9].…”

Association between variants at the GABAAβ2, GABAAα6 and GABAAγ2 gene cluster and alcohol dependence in a Scottish population

“…Furthermore, recent studies have demonstrated that sequences not located at the intron/exon borders, regulate the RNA splicing process. 28 These include several silent exonic polymorphisms [29][30][31][32][33] which do not confer an amino acid change.…”

Mutation analysis of the FAH gene in Israeli patients with tyrosinemia type I

“…This mutation is common among patients of French Canadian origin and was also reported in 45% of the West European patients (Grompe et al, 1994, Ploos van Amstel et al, 1996. The observation of this mutation in patient 3 whose family has resided in the same village for the past 500 years, suggests that the mutation has either occurred multiple times world wide or has originated in the Middle East.…”