Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia typeII

Abstract

Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disorder of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT). We have previously described one deletion and six different point mutations in four RHS patients. We have now analyzed the TAT genes in a further seven unrelated RHS families from Italy, France, the United Kingdom, and the United States. We have established PCR conditions for the amplification of all twelve TAT exons and have screened the products for mutations by direct sequence analysis or by first performing single-strand conformation polymorphism analysis. We have thus identified the presumably pathological mutations in eight RHS alleles, including two nonsense mutations (R57X, E411X) and four amino acid substitutions (R119W, L201R, R433Q, R433W). Only the R57X mutation, which was found in one Scottish and two Italian families, has been previously reported in another Italian family. Haplotype analysis indicates that this mutation, which involves a CpG dinucleotide hot spot, has a common origin in the three Italian families but arose independently in the Scottish family. Two polymorphisms have also been detected, viz., a protein polymorphism, P15S, and a silent substitution S103S (TCG-->TCA). Expression of R433Q and R433W demonstrate reduced activity of the mutant proteins. In all, twelve different TAT gene mutations have now been identified in tyrosinemia type II.

Down-regulation of tyrosine aminotransferase at a frequently deleted region 16q22 contributes to the pathogenesis of hepatocellular carcinoma

“…Mutations in the TAT gene cause a shortage of the enzyme, leading to a toxic accumulation of tyrosine and its byproducts, which can damage the liver, kidneys, nervous system, and other organs and tissues. 6 Tyrosinemia has long been considered an important risk factor for HCC. 7,8 Although this correlation was primarily based on data from tyrosinemia type I, it is fairly reasonable to speculate that loss of TAT may also be a high risk for HCC, because loss of TAT results in similar elevations of tyrosine and its catabolites, as in tyrosinemia type I.…”

The Crystal Structures of Zea mays and Arabidopsis 4-Hydroxyphenylpyruvate Dioxygenase

“…Defects of Tyr catabolism in humans range from relatively mild symptoms in type II tyrosinemia (Huhn et al, 1998;Phornphutkul et al, 2002) to fatal, if untreated, type I tyrosinemia (Russo and O'Regan, 1990;Russo et al, 2001). In type I tyrosinemia a dearth of active fumarylacetoacetase results in the accumulation of fumarylacetoacetate in the liver where it is either saturated or decarboxylated to succinylacetoacetone or succinylacetone, respectively (Lindblad et al, 1977a).…”

Crystal structure of trypanosoma cruzi tyrosine aminotransferase: Substrate specificity is influenced by cofactor binding mode

“…Reduced TAT activity was found in mutations affecting Arg405 R433Q and R433W in human TAT; Hühn et al, 1998!. The guanidinium group of this amino acid is involved in a hydrogen bonding network with the carbonyl oxygen of Glu372, with Glu401 OE2 and with the carbonyl oxygen of residue 34 in the substratebinding domain.…”

“…can readily be explained from the structure template. The exchange of Arg81 for a tryptophan~po-sition 119 in human TAT; Hühn et al, 1998! places a residue with a high spatial requirement at the top of helix a3.…”

“…The mutation should therefore lead to a misfolded protein. Substituting a hydrophobic amino acid with an arginine at position 170~L201R mutation in human TAT; Hühn et al, 1998! places a positive charge in the middle of an extensive hydrophobic cluster consisting of at least 10 residues in the mammalian enzyme.…”