Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II

• Published in: Human genetics 1998-03, Vol.102 (3), p.305-313
• Main Authors: HÜHN, R, STOERMER, H, SCHERER, G, KLINGELE, B, BAUSCH, E, FOIS, A, FARNETANI, M, DI ROCCO, M, BOUE, J, KIRK, J. M, COLEMAN, R
• Format: Article
• Language: English
• Subjects: Adult; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Sequence; Amino Acid Substitution; Aminoacid disorders; Biological and medical sciences; Consanguinity; DNA Mutational Analysis; Errors of metabolism; Escherichia coli - genetics; Exons - genetics; Female; Gene Expression; Haplotypes; Humans; Infant; Infant, Newborn; Italy; Male; Medical sciences; Metabolic diseases; Molecular Sequence Data; Mutation - genetics; Pedigree; Polymerase Chain Reaction - methods; Polymorphism, Single-Stranded Conformational; Recombinant Fusion Proteins; Tyrosine - blood; Tyrosine Transaminase - genetics
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s004390050696

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.