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Molecular studies of mitochondrial acetoacetyl‐coenzyme a thiolase deficiency in the two original families
Author(s) -
Fukao Toshiyuki,
Yamaguchi Seiji,
Scriver Charles R.,
Dunbar Gail,
Wakazono Akihiro,
Kano Masatsugu,
Orii Tadao,
Hashimoto Takashi
Publication year - 1993
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.1380020310
Subject(s) - biology , mutation , genetics , thiolase , frameshift mutation , allele , microbiology and biotechnology , compound heterozygosity , transition (genetics) , proband , exon , point mutation , intron , stop codon , splice site mutation , translation (biology) , gene , messenger rna , alternative splicing , peroxisome
Abstract 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 (A T G to A A G). 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). © 1993 Wiley‐Liss, Inc.