Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene

Kano, Masatsugu; Fukao, Toshiyuki; Yamaguchi, Seiji; Orii, Tadao; Osumi, Takashi; Hashimoto, Takashi

doi:10.1016/0378-1119(91)90623-j

Cited by 51 publications

(34 citation statements)

References 18 publications

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“…Diagnosis is confirmed by measurement of T2 activity on cultured skin fibroblasts (Robinson et al 1979;Zhang et al 2004). T2 deficiency is caused by mutations in the ACAT1 (T2) gene located on chromosome 11q22.3-q23.1 (Fukao et al 1990; Kano et al 1991). T2 deficiency is very heterogeneous at the genotype level, with at least 50 different mutations described (Fukao et al , 1997(Fukao et al , 1998(Fukao et al , 2002(Fukao et al , 2003(Fukao et al , 2008(Fukao et al , 2010aWakazono et al 1995;Nakamura et al 2001;Zhang et al 2004Zhang et al , 2006Sakurai et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1

et al. 2011

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Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects both isoleucine catabolism and ketone body metabolism. The disorder is characterized by intermittent ketoacidotic episodes. We report three Japanese patients. One patient (GK69) experienced two ketoacidotic episodes at the age of 9 months and 3 years, and no further episodes until the age of 25 years. She had two uncomplicated pregnancies. GK69 was a compound heterozygote of the c.431A>C (H144P) and c.1168T>C (S390P) mutations in T2 (ACAT1) gene. She was not suspected of having T2 deficiency during her childhood, but she was diagnosed as T2 deficient at the age of 25 years by enzyme assay using fibroblasts. The other two patients were identical twin siblings who presented their first ketoacidotic crisis simultaneously at the age of 3 years 4 months. One of them (GK77b) died during the first crisis and the other (GK77) survived. Even during severe crises, C5-OH and C5:1 were within normal ranges in their blood acylcarnitine profiles and trace amounts of tiglylglycine and small amounts of 2-methyl-3-hydroxybutyrate were detected in their urinary organic acid profiles. They were H144P homozygotes. This H144P mutation has retained the highest residual T2 activity in the transient expression analysis of mutant cDNA thus far, while the S390P mutation did not retain any residual T2 activity. The "mild" H144P mutation may result in subtle profiles in blood acylcarnitine and urinary organic acid analyses. T2-deficient patients with "mild" mutations have severe ketoacidotic crises but their chemical phenotypes may be subtle even during acute crises.JIMD Reports

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Section: Introductionmentioning

confidence: 99%

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1

et al. 2011

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“…7 B shows the results of transfection into human fibroblasts. In cells transfected with the pCAGGS7-9 control, a chimeric cDNA with the exon 8 sequence was amplified (contron 10, which we previously cloned from a normal individual (8). X indicates XbaI sites.…”

Section: Resultsmentioning

confidence: 99%

“…Human T2 cDNA is about 1.5 kb and encodes the 424-amino acid T2 precursor (7). The 27-kb human T2 gene, with 12 exons and 11 introns (8), is located on chromosome 1 lq22.3-q23.1 (9). In five different families, we identified seven gene mutations responsible for this disease (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel exonic mutation at -13 from 5' splice site causing exon skipping in a girl with mitochondrial acetoacetyl-coenzyme A thiolase deficiency.

Fukao

Yamaguchi²,

Wakazono³

et al. 1994

J. Clin. Invest.

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We identified a novel exonic mutation which causes exon skipping in the mitochondrial acetoacetyl-CoA thiolase (T2) gene from a girl with T2 deficiency (GK07). GKO7 is a compound heterozygote; the maternal allele has a novel G to T transversion at position 1136 causing Gly379 to Val substitution (G379V) of the T2 precursor. In case of in vivo expression analysis, cells transfected with this mutant cDNA showed no evidence of restored T2 activity. The paternal allele was associated with exon 8 skipping at the cDNA level. At the gene level, a C to T transition causing Glnr2 to termination codon (Q272STOP) was identified within exon 8, 13 bp from the 5' splice site of intron 8 in the paternal allele. The mRNA with Q272STOP could not be detected in GKO7 fibroblasts, presumably because pre-mRNA with Q272STOP was unstable because of the premature termination. In vivo splicing experiments revealed that the exonic mutation caused partial skipping of exon 8. This substitution was thought to alter the secondary structure of T2 pre-mRNA around exon 8 and thus impede normal splicing. The role of exon sequences in the splicing mechanism is indicated by the exon skipping which occurred with an exonic mutation. (J. Clin. Invest. 1994. 93:1035-1041.) Key words: 8-ketothiolase deficiency * exon skipping -molecular basis * in vivo splicing experiment * organic aciduria

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“…Human T2 cDNA is about 1.5 kb long and is encoded for a precursor of 427 amino acids, including a 33-amino acid leader polypeptide. The T2 gene spans approximately 27 kb, contains 12 exons (Kano et aL, 1991), and is located at 11q22.3-23.1 (Masuno et al, 1992).…”

Section: Z Fl-ketothiolase Deficiencymentioning

confidence: 99%

Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene

Cited by 51 publications

References 18 publications

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1

Identification of a novel exonic mutation at -13 from 5' splice site causing exon skipping in a girl with mitochondrial acetoacetyl-coenzyme A thiolase deficiency.

Molecular basis of zellweger syndrome,β-ketothiolase deficiency and mucopolysaccharidoses

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