University of Oulu

Abdelkreem, E, Harijan, RK, Yamaguchi, S, Wierenga, RK, Fukao, T. Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency. Human Mutation. 2019; 40: 1641– 1663.

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

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Author: Abdelkreem, Elsayed1,2; Harijan, Rajesh K.3; Yamaguchi, Seiji4;
Organizations: 1Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
2Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt
3Department of Biochemistry, Albert Einstein College of Medicine, New York, New York
4Department of Pediatrics, Shimane University School of Medicine, Izumo, Japan
5Biocenter Oulu and FBMM, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.7 MB)
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Language: English
Published: John Wiley & Sons, 2019
Publish Date: 2020-02-26


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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Series: Human mutation
ISSN: 1059-7794
ISSN-E: 1098-1004
ISSN-L: 1059-7794
Volume: 40
Issue: 10
Pages: 1641 - 1663
DOI: 10.1002/humu.23831
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
Funding: This research was supported by a Grant‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant number 16K09962), by AMED under grant number JP17ek0109276, and by Health and Labor Sciences Research Grants (H29‐nanchitou(nan)‐ippan‐051) for research on rare and intractable diseases.
Copyright information: © 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.