Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1991 Aug;49(2):429–434.

Occurrence of a Tyr393----Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population.

C R Fisher 1, C W Fisher 1, D T Chuang 1, R P Cox 1
PMCID: PMC1683290  PMID: 1867199

Abstract

Maple syrup urine disease (MSUD) is caused by a deficiency in the mitochondrial branched-chain alpha-keto acid dehydrogenase complex. The incidence of MSUD in the Philadelphia Mennonites is 1/176 births resulting from consanguinity. In this study, we amplified cDNAs for the decarboxylase E1 alpha subunit of the branched-chain alpha-keto acid dehydrogenase complex from a classical MSUD patient and from an obligatory heterozygote of a Mennonite family by the PCR. Sequencing of the amplified cDNAs disclosed at codon 393 of the mature E1 alpha polypeptide a base substitution changing a tyrosine (encoded by TAC) to an asparagine residue (encoded by AAC), which is designated Y393N. A segment of the E1 alpha gene containing the 5' portion of exon 9 was amplified. Probing of the amplified genomic DNA with allele-specific oligonucleotide probes showed that the mutation in the E1 alpha gene was homozygous in six Mennonites affected with classical MSUD and was present in heterozygous carriers. The identification of the MSUD mutation in the Philadelphia Mennonites will facilitate diagnosis and carrier detection for this population.

Full text

PDF
429

Images in this article

431Figure 1
on p.431
432Figure 2
on p.432

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Chase G. A. The TSD gene among Ashkenazic Jews: founder effect and genetic drift. Prog Clin Biol Res. 1977;18:107–110. [PubMed] [Google Scholar]
  2. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  3. Chuang D. T., Cox R. P. Enzyme assays with mutant cell lines of maple syrup urine disease. Methods Enzymol. 1988;166:135–146. doi: 10.1016/s0076-6879(88)66020-4. [DOI] [PubMed] [Google Scholar]
  4. Cooper D. N., Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. doi: 10.1007/BF00278187. [DOI] [PubMed] [Google Scholar]
  5. Fisher C. W., Chuang J. L., Griffin T. A., Lau K. S., Cox R. P., Chuang D. T. Molecular phenotypes in cultured maple syrup urine disease cells. Complete E1 alpha cDNA sequence and mRNA and subunit contents of the human branched chain alpha-keto acid dehydrogenase complex. J Biol Chem. 1989 Feb 25;264(6):3448–3453. [PubMed] [Google Scholar]
  6. Hartl F. U., Pfanner N., Nicholson D. W., Neupert W. Mitochondrial protein import. Biochim Biophys Acta. 1989 Jan 18;988(1):1–45. doi: 10.1016/0304-4157(89)90002-6. [DOI] [PubMed] [Google Scholar]
  7. Hu C. W., Lau K. S., Griffin T. A., Chuang J. L., Fisher C. W., Cox R. P., Chuang D. T. Isolation and sequencing of a cDNA encoding the decarboxylase (E1)alpha precursor of bovine branched-chain alpha-keto acid dehydrogenase complex. Expression of E1 alpha mRNA and subunit in maple-syrup-urine-disease and 3T3-L1 cells. J Biol Chem. 1988 Jun 25;263(18):9007–9014. [PubMed] [Google Scholar]
  8. Indo Y., Kitano A., Endo F., Akaboshi I., Matsuda I. Altered kinetic properties of the branched-chain alpha-keto acid dehydrogenase complex due to mutation of the beta-subunit of the branched-chain alpha-keto acid decarboxylase (E1) component in lymphoblastoid cells derived from patients with maple syrup urine disease. J Clin Invest. 1987 Jul;80(1):63–70. doi: 10.1172/JCI113064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Matsuda I., Nobukuni Y., Mitsubuchi H., Indo Y., Endo F., Asaka J., Harada A. A T-to-A substitution in the E1 alpha subunit gene of the branched-chain alpha-ketoacid dehydrogenase complex in two cell lines derived from Menonite maple syrup urine disease patients. Biochem Biophys Res Commun. 1990 Oct 30;172(2):646–651. doi: 10.1016/0006-291x(90)90723-z. [DOI] [PubMed] [Google Scholar]
  10. Mitchell G. A., Brody L. C., Sipila I., Looney J. E., Wong C., Engelhardt J. F., Patel A. S., Steel G., Obie C., Kaiser-Kupfer M. At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns. Proc Natl Acad Sci U S A. 1989 Jan;86(1):197–201. doi: 10.1073/pnas.86.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  12. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Yeaman S. J. The 2-oxo acid dehydrogenase complexes: recent advances. Biochem J. 1989 Feb 1;257(3):625–632. doi: 10.1042/bj2570625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Zhang B., Crabb D. W., Harris R. A. Nucleotide and deduced amino acid sequence of the E1 alpha subunit of human liver branched-chain alpha-ketoacid dehydrogenase. Gene. 1988 Sep 15;69(1):159–164. doi: 10.1016/0378-1119(88)90390-3. [DOI] [PubMed] [Google Scholar]
  15. Zhang B., Edenberg H. J., Crabb D. W., Harris R. A. Evidence for both a regulatory mutation and a structural mutation in a family with maple syrup urine disease. J Clin Invest. 1989 Apr;83(4):1425–1429. doi: 10.1172/JCI114033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Zhang B., Kuntz M. J., Goodwin G. W., Harris R. A., Crabb D. W. Molecular cloning of a cDNA for the E1 alpha subunit of rat liver branched chain alpha-ketoacid dehydrogenase. J Biol Chem. 1987 Nov 5;262(31):15220–15224. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES