NOVEL AND RECURRENT TYROSINE AMINOTRANSFERASE GENE-MUTATIONS IN TYROSINEMIA TYPE-II

Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disorder of a utosomal recessive inheritance characterized by keratitis, palmoplanta r hyperkeratosis, mental retardation, and elevated blood tyrosine leve ls, The disease results from deficiency in hepatic tyrosine aminotrans ferase (TAT). We have previously described one deletion and six differ ent point mutations in four RHS patients. We have now analyzed the TAT genes in a further seven unrelated RHS families from Italy, France, t he United Kingdom, and the United States. We have established PCR cond itions for the amplification of all twelve TAT exons and have screened the products for mutations by direct sequence analysis or by first pe rforming single-strand conformation polymorphism analysis, We have thu s identified the presumably pathological mutations in eight RHS allele s, including two nonsense mutations (R57X, E411X) and four amino acid substitutions (R119W, L201R, R433Q, R433W). Only the R57X mutation, wh ich was found in one Scottish and two Italian families, has been previ ously 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 i n 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 t he mutant proteins. In all, twelve different TAT gene mutations have n ow been identified in tyrosinemia type II.