14-3-3ε Gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum

Bo Chang, Carlos Gorbea, George T Lezin, Ling Li, Lishen Shan, Norio Sakai, Shigetoyo Kogaki, Takanobu Otomo, Takeshi Okinaga, Akiko Hamaoka, Xianyi Yu, Yukiko Hata, Naoki Nishida, H. Joseph Yost, Neil E. Bowles, Luca Brunelli, Fukiko Ichida

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller-Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans. Methods and results: In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c- 458G > T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The - 458G > T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50%. Increased binding of an inhibitory C/EBPβ isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPβ is a key regulator of YWHAE. Conclusions: These data suggest that the - 458G > T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalGene
Volume515
Issue number1
DOIs
StatePublished - Feb 15 2013

Fingerprint

CCAAT-Enhancer-Binding Proteins
Corpus Callosum
Cardiomyopathies
Morphogenesis
Classical Lissencephalies and Subcortical Band Heterotopias
Genes
14-3-3 Proteins
Trabecular Meshwork
Response Elements
DNA Sequence Analysis
Protein Isoforms
Pediatrics
Mutation
Brain
Proteins

Keywords

  • 14-3-3 proteins
  • Brain development
  • Cardiomyopathy
  • Myocardial morphogenesis
  • Ventricular noncompaction
  • YWHAE variants

ASJC Scopus subject areas

  • Genetics

Cite this

14-3-3ε Gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum. / Chang, Bo; Gorbea, Carlos; Lezin, George T; Li, Ling; Shan, Lishen; Sakai, Norio; Kogaki, Shigetoyo; Otomo, Takanobu; Okinaga, Takeshi; Hamaoka, Akiko; Yu, Xianyi; Hata, Yukiko; Nishida, Naoki; Yost, H. Joseph; Bowles, Neil E.; Brunelli, Luca; Ichida, Fukiko.

In: Gene, Vol. 515, No. 1, 15.02.2013, p. 173-180.

Research output: Contribution to journalArticle

Chang, B, Gorbea, C, Lezin, GT, Li, L, Shan, L, Sakai, N, Kogaki, S, Otomo, T, Okinaga, T, Hamaoka, A, Yu, X, Hata, Y, Nishida, N, Yost, HJ, Bowles, NE, Brunelli, L & Ichida, F 2013, '14-3-3ε Gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum', Gene, vol. 515, no. 1, pp. 173-180. https://doi.org/10.1016/j.gene.2012.12.049
Chang, Bo ; Gorbea, Carlos ; Lezin, George T ; Li, Ling ; Shan, Lishen ; Sakai, Norio ; Kogaki, Shigetoyo ; Otomo, Takanobu ; Okinaga, Takeshi ; Hamaoka, Akiko ; Yu, Xianyi ; Hata, Yukiko ; Nishida, Naoki ; Yost, H. Joseph ; Bowles, Neil E. ; Brunelli, Luca ; Ichida, Fukiko. / 14-3-3ε Gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum. In: Gene. 2013 ; Vol. 515, No. 1. pp. 173-180.
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abstract = "Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller-Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans. Methods and results: In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c- 458G > T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The - 458G > T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50{\%}. Increased binding of an inhibitory C/EBPβ isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPβ is a key regulator of YWHAE. Conclusions: These data suggest that the - 458G > T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies.",
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T1 - 14-3-3ε Gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum

AU - Chang, Bo

AU - Gorbea, Carlos

AU - Lezin, George T

AU - Li, Ling

AU - Shan, Lishen

AU - Sakai, Norio

AU - Kogaki, Shigetoyo

AU - Otomo, Takanobu

AU - Okinaga, Takeshi

AU - Hamaoka, Akiko

AU - Yu, Xianyi

AU - Hata, Yukiko

AU - Nishida, Naoki

AU - Yost, H. Joseph

AU - Bowles, Neil E.

AU - Brunelli, Luca

AU - Ichida, Fukiko

PY - 2013/2/15

Y1 - 2013/2/15

N2 - Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller-Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans. Methods and results: In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c- 458G > T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The - 458G > T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50%. Increased binding of an inhibitory C/EBPβ isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPβ is a key regulator of YWHAE. Conclusions: These data suggest that the - 458G > T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies.

AB - Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller-Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans. Methods and results: In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c- 458G > T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The - 458G > T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50%. Increased binding of an inhibitory C/EBPβ isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPβ is a key regulator of YWHAE. Conclusions: These data suggest that the - 458G > T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies.

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KW - YWHAE variants

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