Molecular studies of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in the two original families.
We describe mutations identified in stored skin fibroblast cell lines from two original probands (JB and JM), first reported with 2-methylacetoacetic aciduria, and shown later to have a deficiency of the K(+)-activated enzyme, mitochondrial acetoacetyl-coenzyme A thiolase (T2). JB is homozygous for a 4-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 (Ggcag/gt) 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 (IVS11nt2) causes an unstable T2 polypeptide and the JM mutation (M1K) severely impairs T2 mRNA translation. The JB allele associates with Dutch ancestry (no consanguinity) and the JM allele with Chilean ancestry (distant consanguinity).
Fukao
T
T
Department of Pediatrics, Gifu University School of Medicine, Japan.
Yamaguchi
S
S
Scriver
C R
CR
Dunbar
G
G
Wakazono
A
A
Kano
M
M
Orii
T
T
Hashimoto
T
T
D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency* / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005347:Fibroblasts / Q000201:enzymology; D015870:Gene Expression; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D017354:Point Mutation
D004247:DNA; D000101:Acetyl-CoA C-Acetyltransferase