title: 14-3-3ε gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum.
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.
  
  
  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.
authors.affiliation: Department of Pediatrics, University of Toyama, Toyama, Japan.
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Carlos
authors.initials: C
authors.lastname: Gorbea
authors.forename: George
authors.initials: G
authors.lastname: Lezin
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Lishen
authors.initials: L
authors.lastname: Shan
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
authors.forename: Shigetoyo
authors.initials: S
authors.lastname: Kogaki
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otomo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okinaga
authors.forename: Akiko
authors.initials: A
authors.lastname: Hamaoka
authors.forename: Xianyi
authors.initials: X
authors.lastname: Yu
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hata
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishida
authors.forename: H Joseph
authors.initials: HJ
authors.lastname: Yost
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Luca
authors.initials: L
authors.lastname: Brunelli
authors.forename: Fukiko
authors.initials: F
authors.lastname: Ichida
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D061085:Agenesis of Corpus Callosum / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003337:Corpus Callosum / Q000378:metabolism*; D005091:Exons; D017809:Fatal Outcome; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000235:genetics*; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic
chemical_list: D048948:14-3-3 Proteins; C482983:YWHAE protein, human