Glycogen storage disease type Ia: Molecular diagnosis of 51 Japanese patients and characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblastoid cells

Jun Akanuma, Toshinori Nishigaki, Kunihiro Fujii, Yoichi Matsubara, Koji Inui, Kazutoshi Takahashi, Shigeo Kure, Yoichi Suzuki, Toshihiro Ohura, Shigeaki Miyabayashi, Eishin Ogawa, Kazuie Iinuma, Shintaro Okada, Kuniaki Narisawa

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of glucose-6- phosphatase (G6Pase) that is expressed in the liver, kidney, and intestinal mucosa. Clinical manifestations include short stature, hepatomegaly, hypoglycemia, hyperuricemia, and lactic acidemia. To elucidate a spectrum of the G6Pase gene mutations and their frequencies, we analyzed mutations in 51 unrelated Japanese patients with GSD-Ia. The most prevalent mutation was g727t, accounting for 88 of 102 mutant alleles examined, followed by R170X mutation, which accounted for 6 mutant alleles, and R83H mutation which was observed in 3 mutant alleles. In addition, 3 different, novel mutations, IVS1-1g<a, Gly122-to-Asp (G122D) and His179-to-Pro (H179P), were identified. We were able to detect 'ectopically' transcribed G6Pase-mRNA in Epstein-Barr virus-transformed lymphoblastoid cells and observed aberrant mRNA splicing associated with the g727t and IVS1-1g<a mutations. To our knowledge, this is the first report that ectopic expression can be utilized for the characterization of GSD-Ia mutations. Our findings suggest that a screening for the g727t, R170X, and R83H mutations by simple DNA-based diagnostic methods can detect 95% of the G6Pase mutant alleles in Japanese patients with GSD-Ia, and remaining mutations can be identified and characterized by the direct sequencing of genomic DNA and/or the analysis of ectopically expressed mRNA. The noninvasive molecular diagnosis for GSD-Ia may ultimately replace the conventional means of enzymatic diagnosis that re. quires liver biopsy. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)107-112
Number of pages6
JournalAmerican journal of medical genetics
Volume91
Issue number2
DOIs
Publication statusPublished - 2000

Keywords

  • DNA- based diagnosis
  • Ectopic transcription
  • Glucose-6-phosphatase
  • Glycogen storage disease type Ia
  • Mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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