MUTATION ANALYSIS OF THE 6-PYRUVOYL-TETRAHYDROPTERIN SYNTHASE GENE INCHINESE HYPERPHENYLALANINEMIA CAUSED BY TETRAHYDROBIOPTERIN SYNTHESISDEFICIENCY

Hyperphenylalaninemia (HPA) may be caused by deficiency of phenylalani ne hydroxylase or tetrahydrobiopterin (BH4), the essential cofactor fo r the aromatic amino acid hydroxylases. 6-Pyruvoyl-tetrahydropterin sy nthase (PTPS) deficiency is a major cause of BH4 deficient HPA.]in thi s study, seven single base mutations at nucleotides 73 (C>G), 155 (A>G ), 166 (G>A), 209 (T>A), 259 (C>T), 286 (G>A), and 317 (C>T) on PTPS c DNA were detected in Chinese PTPS-deficient HPA by polymerase chain re action and solid phase DNA sequencing. These nucleotide alterations re sult in R25G, N52S, V56M, V70D, P87D, D9GN, and T106M amino acid subst itutions, respectively The R25G, V56M, V70D, and T106M were novel muta tions found in PTPS gene. By analysis of 38 PTPS mutant alleles from 1 9 unrelated Chinese PTPS deficient HPA families, the allele frequency of these mutations in Chinese PTPS-deficient HPA were determined to be similar to 5.3% (R25G), 34.2% (N52S), 7.9% (V56M), 2.6% (V70D), 36.8% (P87S), 7.9% (D96N), and 2.6% (T106M), respectively. Two common mutat ions, N52S and P87S, were found to account for 71% of the Chinese PTPS mutant alleles. The N52S mutation accounts for 48% of the southern Ch inese PTPS mutation, but only one (9%) of the northern Chinese PTPS mu tant allele was found to be N52S, which suggested that the N52S mutati on might be southern Chinese, Clinically, the V56M mutation was found to associate with the mild form of PTPS deficiency. However, the R25G, N52S, P87S, and D96N were found mainly in the patients with severe cl inical symptom. Using polymerase chain reaction-based mutation analysi s, a fetus at risk of PTPS deficiency was diagnosed prenatally to be a carrier of N52S mutation. (C) 1998 Wiley-Liss, Inc.