Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1989 April; 83(4): 1425–1429.
PMCID: PMC303839

Evidence for both a regulatory mutation and a structural mutation in a family with maple syrup urine disease.


Maple syrup urine disease (MSUD) results from a deficiency of branched chain alpha-ketoacid dehydrogenase (BCKDH). We have studied the etiology of MSUD by determining the enzyme activity, protein, and mRNA levels of BCKDH in fibroblasts from a classic MSUD patient and his parents. By enzymatic amplification of the patient's mRNA followed by cloning and DNA sequencing, we have identified a T to A transversion that alters a tyrosine to an asparagine at residue 394 of the E1 alpha subunit. Amplification of both mRNA and genomic DNA, in combination with allele-specific oligonucleotide hybridization, demonstrated that the father was heterozygous for this mutant allele. The mother was homozygous for the allele encoding the normal Tyr394, but expressed only about half of the normal level of mRNA and protein. The patient was genetically heterozygous for this altered allele, although only the abnormal allele was expressed as mRNA. We conclude that the patient was a compound heterozygote, inheriting an allele encoding an abnormal E1 alpha from the father, and an allele from the mother containing a cis-acting defect in regulation which abolished the expression of one of the E1 alpha alleles. Our results revealed for the first time that a case of MSUD was caused by structural and regulatory mutations involving the E1 alpha subunit.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.0M), or click on a page image below to browse page by page.

Images in this article

Click on the image to see a larger version.

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation