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cDNA Cloning of the E1α Subunit of the Branshed‐Chain α‐Keto Acid Dehydrogenase and Elucidation of a Molecular Basis for Maple Syrup Urine Disease a
Author(s) -
ZHANG BEI,
KUNTZ MARTHA J.,
GOODWIN GARY W.,
EDENBERG HOWARD J.,
CRABB DAVID W.,
HARRIS ROBERT A.
Publication year - 1989
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1989.tb14991.x
Subject(s) - maple syrup urine disease , complementary dna , biology , microbiology and biotechnology , protein subunit , allele , molecular cloning , peptide sequence , amino acid , gene , compound heterozygosity , biochemistry , enzyme , genetics , leucine
We have cloned cDNAs encoding human and rat liver BCKDH E1 alpha subunits and deduced the primary structure of the mature protein. The sequences of the cDNA and protein are highly conserved between the two species. Significant sequence similarity has also been found between human BCKDH and PDH E1 alpha subunits. We have studied the molecular basis of MSUD by determining the enzyme activity and levels of BCKDH protein and mRNA, and by enzymatic amplification and sequencing of BCKDH E1 alpha-specific mRNA, from an MSUD patient and his parents. Different mutant alleles were identified in the two parents. The patient was a compound heterozygote, inheriting an allele encoding an abnormal E1 alpha from the father and an allele containing a defect in regulation from the mother. Our results demonstrate that a case of MSUD was caused by structural and regulatory mutations involving the E1 alpha subunit.