Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): Identification of a Km mutant and an analysis of the mutational sites in the structure

Sakurai, Satomi; Fukao, Toshiyuki; Haapalainen, Antti M.; Zhang, Gaixiu; Yamada, Keitaro; Lilliu, Franco; Yano, Shoji; Robinson, P.H.; Gibson, Michael K.; Wanders, Ronald J. A.; Mitchell, Grant A.; Wierenga, Rik K.; Kondo, Naomi

doi:10.1016/j.ymgme.2006.12.002

Cited by 17 publications

(24 citation statements)

References 26 publications

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“…The incubation temperature affects posttranslational modifications of protein structure, including protein folding and stability. Incubation at a lower temperature during expression may considerably stabilize mutant T2 proteins (Sakurai et al 2007). This temperature-sensitive phenomenon was previously described in several ACAT1 mutations, such as p.Ala132Gly, p.Gln145Glu, p.Glu215-del, p.Glu252del, and p.Thr297Met (Fukao et al 2001;Zhang et al 2004;Sakurai et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Although having no residual enzymatic activities, some mutant T2 proteins are soluble. For example, p.Gly152Ala and p.Asn158Asp were detected by expression at 30 C, whereas others, such as p. Arg208Gln, p.Tyr219His, and p.Asn282His, could be identified in supernatants by expression not only at 37 C but also at 40 C (Zhang et al 2004;Sakurai et al 2007). A distinction between genetic mutations based on their residual enzymatic activities may become important for some prospective therapeutic modalities.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

Abdelkreem

Akella

Dave³

et al. 2016

JIMD Reports

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Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase (T2) deficiency) is an inherited disease of isoleucine catabolism and ketone body utilization caused by ACAT1 mutations. We identified ten Indian patients who manifested with ketoacidotic episodes of variable severity. The patients showed increased urinary excretion of isoleucine-catabolic intermediates: 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

Abdelkreem

Akella

Dave³

et al. 2016

JIMD Reports

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“…Recent evidence indicates that the c.622C>T variant has been introduced by an ancient common founder to Vietnamese Kinh ethnic population 1900–2500 years ago (Nguyen et al, ). This highly conserved residue is changed into glutamine (c.623G>A, p.Arg208Gln) in two other families (Sakurai et al, ). The importance of this residue for the enzymatic function is discussed in subsequent sections.…”

Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

et al. 2019

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Mitochondrial acetoacetyl‐CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. It typically manifests with episodic ketoacidosis. The presence of isoleucine‐derived metabolites is the key marker for biochemical diagnosis. To date, 105 ACAT1 variants have been reported in 149 T2‐deficient patients. The 56 disease‐associated missense ACAT1 variants have been mapped onto the crystal structure of T2. Almost all these missense variants concern residues that are completely or partially buried in the T2 structure. Such variants are expected to cause T2 deficiency by having lower in vivo T2 activity because of lower folding efficiency and/or stability. Expression and activity data of 30 disease‐associated missense ACAT1 variants have been measured by expressing them in human SV40‐transformed fibroblasts. Only two variants (p.Cys126Ser and p.Tyr219His) appear to have equal stability as wild‐type. For these variants, which are inactive, the side chains point into the active site. In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype. This could be related to variable remaining residual T2 activity in vivo and has important clinical implications concerning disease management and newborn screening.

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“…Transient expression of T2 cDNAs was performed using a pCAGGS eukaryote expression vector (Niwa et al 1991), as described (Sakurai et al 2007). After transfection, cells were cultured at 37 C or 40 C for 48 h, then harvested and kept at À80 C until use.…”

Section: Transient Expression Analysis Of Mutant Cdnasmentioning

confidence: 99%

“…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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Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): Identification of a Km mutant and an analysis of the mutational sites in the structure

Cited by 17 publications

References 26 publications

Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

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

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