2016年5月
Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan
MOLECULAR GENETICS AND METABOLISM
- 巻
- 118
- 号
- 1
- 開始ページ
- 9
- 終了ページ
- 14
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.ymgme.2015.12.011
- 出版者・発行元
- ACADEMIC PRESS INC ELSEVIER SCIENCE
Background: Since the first case was detected in 2000, there has been a remarkable increase in Japanese patients diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Genetic analysis has revealed a spectrum of mutations that is quite different from those observed in Caucasian populations. In 2014, Japan initiated nationwide newborn screening (NBS) for MCAD using tandem mass spectrometry (MS/MS). It is an urgent issue to assess the risk of acute metabolic decompensation from the respective novel mutations found thus far.
Methods: To evaluate the pathogenic effect of each mutation, we established a eukaryotic cell expression system and prepared 11 mutant proteins identified in five symptomatic patients and eight MS/MS-NBS-positive newborns, as well as two common Caucasian mutations, p.K329E (c.985G > A) and p.Y67H (c.157C > T) for comparison.
Results: The expression of four mutant proteins (p.Q45R, p.P92L, p.P128X and p.Y397N) were severely impaired, whereas the others expressed normally, as did p.K329E and p.Y67H. Based on their dehydrogenase activities toward n-octanoyl-CoA, we determined three mutations (p.R53C, p.R281S and p.G362E) to be disease-causing, two mutations having (p.R17H and p.M274V) to be of marginal risk, and two mutations (p.K271E and p.I416T) as benign. Their allele-specific activities were as a whole in accordance with those estimated from the results of measurement in peripheral blood mononuclear cells.
Conclusion: As most of the mutations detected in the Japanese population are unique, prudent genetic and enzymatic analysis is essential to precisely evaluate the latent risk of clinical onset for screening-positive newborns. (C) 2015 Elsevier Inc All rights reserved.
Methods: To evaluate the pathogenic effect of each mutation, we established a eukaryotic cell expression system and prepared 11 mutant proteins identified in five symptomatic patients and eight MS/MS-NBS-positive newborns, as well as two common Caucasian mutations, p.K329E (c.985G > A) and p.Y67H (c.157C > T) for comparison.
Results: The expression of four mutant proteins (p.Q45R, p.P92L, p.P128X and p.Y397N) were severely impaired, whereas the others expressed normally, as did p.K329E and p.Y67H. Based on their dehydrogenase activities toward n-octanoyl-CoA, we determined three mutations (p.R53C, p.R281S and p.G362E) to be disease-causing, two mutations having (p.R17H and p.M274V) to be of marginal risk, and two mutations (p.K271E and p.I416T) as benign. Their allele-specific activities were as a whole in accordance with those estimated from the results of measurement in peripheral blood mononuclear cells.
Conclusion: As most of the mutations detected in the Japanese population are unique, prudent genetic and enzymatic analysis is essential to precisely evaluate the latent risk of clinical onset for screening-positive newborns. (C) 2015 Elsevier Inc All rights reserved.
- リンク情報
-
- DOI
- https://doi.org/10.1016/j.ymgme.2015.12.011
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/26947917
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000375741500003&DestApp=WOS_CPL
- URL
- http://orcid.org/0000-0002-2479-3178
- ID情報
-
- DOI : 10.1016/j.ymgme.2015.12.011
- ISSN : 1096-7192
- eISSN : 1096-7206
- ORCIDのPut Code : 63302508
- PubMed ID : 26947917
- Web of Science ID : WOS:000375741500003