Mutation and polymorphic marker analyses of 65K- And 67K-glutamate decarboxylase genes in two families with pyridoxine-dependent epilepsy

Shigeo Kure, Yoshiyuki Sakata, Shigeaki Miyahayashi, Kazutoshi Takahashi, Toshikatsu Shinka, Yoichi Matsubara, Hisao Hoshino, Kuniaki Narisawa

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Pyridoxine-dependent epilepsy is a disease inherited as an autosomal recessive trait, characterized by rapid response to pharmacological dosages of pyridoxine. The defect has been suggested to reside in glutamate decarboxylase (GAD), since a mutant GAD with an abnormally high Km for a cofactor, pyridoxal phosphate, could not synthesize an adequate amount of γ-amino butyric acid [Scriver and Whelan (1969) Ann NY Acad Sci 166: 83]. To test this hypothesis, we studied two affected families by screening for mutations in the GAD mRNA and by analyzing a polymorphic marker in the GAD gene. Since two forms of GAD, GAD65 and GAD67, have been identified in human brain, we analyzed both forms. To overcome the limited accessibility of brain tissues, we utilized the minute amounts of GAD mRNAs ectopically transcribed in lymphoblasts. The ectopic GAD transcripts were amplified by reversetranscription-mediated, nested polymerase chain reaction for mutation analysis. Two and three base substitutions were found in GAD65 and GAD67 cDNAs, respectively. All of them were, however, polymorphisms that were also found in control subjects. We then examined a (CA) repeat polymorphism in the GAD65 gene and found that different maternal alleles were transmitted to two affected sibs in one family. Thus, an etiological mechanism other than a Km mutant GAD is responsible for pyridoxine-dependent epilepsy.

Original languageEnglish
Pages (from-to)128-131
Number of pages4
JournalJournal of Human Genetics
Volume43
Issue number2
DOIs
Publication statusPublished - 1998

Keywords

  • Ectopic transcripts
  • Familial analysis CA repeat
  • K mutant
  • cDNA sequence

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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