Molecular analysis of dihydropteridine reductase deficiency: Identification of two novel mutations in Japanese patients

Hiroyuki Ikeda, Yoichi Matsubara, Hitoshi Mikami, Shigeo Kure, Misao Owada, Tamara Gough, Peter M. Smooker, Marion Dobbs, Hans Henrik M. Dahl, Richard G.H. Cotton, Kuniaki Narisawa

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Mutations in the dihydropteridine reductase (DHPR) gene result in hyperphenylalaninaemia and deficiency of various neurotransmitters in the central nervous system, causing severe neurological symptoms. We studied two Japanese patients with DHPR deficiency and identified a missense and a splicing error mutation, respectively. A homozygous missense mutation (tryptophan36-to-arginine) was detected in patient 1. The mutation abolished DHPR activity according to in vitro expression studies. The DHPR mRNA in patient 2 was markedly decreased. Reverse transcription-polymerase chain reaction of the mRNA generated a cDNA fragment with a 152-bp insertion. The inserted sequence contained a termination codon, which was likely to affect the stability of the mRNA. Analysis of genomic DNA showed that the insertion was derived from putative intron 3 of the DHPR gene, and an intronic A-to-G substitution was present adjacent to the 3'-end of the inserted sequence. The nucleotide change generated a sequence similar to an RNA splice donor site and probably activated an upstream cryptic acceptor site, thus producing an abnormal extra exon.

Original languageEnglish
Pages (from-to)637-642
Number of pages6
JournalHuman Genetics
Volume100
Issue number5-6
DOIs
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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