Journal of Inherited Metabolic Disease

, Volume 22, Issue 4, pp 414–427

4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency

  • L. K. Medina-Kauwe
  • A. J. Tobin
  • L. De Meirleir
  • J. Jaeken
  • C. Jakobs
  • W. L. Nyhan
  • K. M. Gibson
Article

Abstract

4-Aminobutyrate aminotransferase (GABA-transaminase, GABA-T, EC 2.6.1.19) deficiency (McKusick 137150), an inborn error of GABA degradation, has until now been documented in only a single Flemish child. Compared to the other defects of GABA degradation, succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.24) deficiency with >150 patients (McKusick 271980) and pyridoxine-dependent seizures with >100 patients ('putative'glutamic acid decarboxylase (GAD, EC 4.1.1.15) deficiency; McKusick 266100), GABA-T deficiency is very rare. We present a summary of the clinical, biochemical, enzymatic and molecular findings on the index proband, and a recently identified second patient, with GABA-T deficiency. The phenotype in both included psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures and electroencephalographic abnormalities. In an effort to elucidate the molecular basis of GABA-T deficiency, we isolated and characterized a 1.5kb cDNA encoding human GABA-T, in addition to a 41kb genomic clone which encompassed the GABA-T coding region. Standard methods of cloning and sequencing revealed an A-to-G transition at nucleotide 754 of the coding region in lymphoblast cDNAs derived from the index proband. This mutation resulted in substitution of an invariant arginine at amino acid 220 by lysine. Expression of the mutant in E. coli, followed by isolation and enzymatic characterization of the recombinant protein, revealed an enzyme whose Vmax was reduced to 25% of wild-type activity. The patient and father were heterozygous for this allele; the second allele in the patient remains unidentified. Genomic Southern analysis revealed that the second proband most likely harbours a deletion in the 3′region of the GABA-T gene.

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Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • L. K. Medina-Kauwe
    • 1
  • A. J. Tobin
    • 2
  • L. De Meirleir
    • 3
  • J. Jaeken
    • 4
  • C. Jakobs
    • 5
  • W. L. Nyhan
    • 6
  • K. M. Gibson
    • 7
  1. 1.Institute for Genetic MedicineUniversity of CaliforniaLos AngelesUSA
  2. 2.Departments of Physiological Science and Neurology, and the Brain Research and Molecular Biology InstitutesUniversity of CaliforniaLos AngelesUSA
  3. 3.Department of Pediatric Neurology, Academic HospitalFree UniversityBrusselsBelgium
  4. 4.Department of PediatricsCatholic University of LeuvenBelgium
  5. 5.Departments of Clinical Chemistry and Pediatrics, Academic HospitalFree University of AmsterdamThe Netherlands
  6. 6.Department of PediatricsUniversity of CaliforniaSan Diego, La JollaUSA
  7. 7.Department of Molecular and Medical Genetics, Biochemical Genetics LaboratoryOregon Health Sciences UniversityPortlandUSA

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