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Molecular studies of mitochondrial acetoacetyl-coenzyme a thiolase deficiency in the two original families

✍ Scribed by Toshiyuki Fukao; Seiji Yamaguchi; Charles R. Scriver; Gail Dunbar; Akihiro Wakazono; Masatsugu Kano; Tadao Orii; Takashi Hashimoto

Publisher: John Wiley and Sons
Year: 1993
Tongue: English
Weight: 652 KB
Volume: 2
Category: Article
ISSN: 1059-7794
DOI: 10.1002/humu.1380020310

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✦ Synopsis

Communicated by R.G.H. Cotton

We describe mutations identified in stored skin fibroblast cell lines from two original prohands (JB and JM), first reported with 2methylacetoacetic aciduria, and shown later to have a deficiency of the K+ -activated enzyme, mitochondrial acetoacetyl-coenzyme A thiolase (T2). JB is homozygous for a %base insertion (GCAG) which is derived mutation. The primary mutation is an AG/gt to AG/gc transition at the 5'-splice-junction site in intron 11. An alternative splice site 4 bp downstream (Ggcadgt) is used which causes a frame shift and replaces 39 C-terminal residues by 70 nonfunctional residues. JM is homozygous for a mutation in the translation-initiation codon (ATG to AAG). By expression analyses the JB mutation (IVSllnt2) causes an unstable T2 polypeptide and the JM mutation (MlK) severely impairs T 2 mRNA translation. The JB allele associates with Dutch ancestry (no consanguinity) and the JM allele with Chilean ancestry (distant consanguinity).

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