title: MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus.
abstract: Cardiac left ventricular outflow tract (LVOT) defects represent a common but heterogeneous subset of congenital heart disease for which gene identification has been difficult. We describe a 46,XY,t(1;5)(p36.11;q31.2)dn translocation carrier with pervasive developmental delay who also exhibited LVOT defects, including bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and patent ductus arteriosus (PDA). The 1p breakpoint disrupts the 5' UTR of AHDC1, which encodes AT-hook DNA-binding motif containing-1 protein, and AHDC1-truncating mutations have recently been described in a syndrome that includes developmental delay, but not congenital heart disease [Xia, F., Bainbridge, M.N., Tan, T.Y., Wangler, M.F., Scheuerle, A.E., Zackai, E.H., Harr, M.H., Sutton, V.R., Nalam, R.L., Zhu, W. et al. (2014) De Novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet., 94, 784-789]. On the other hand, the 5q translocation breakpoint disrupts the 3' UTR of MATR3, which encodes the nuclear matrix protein Matrin 3, and mouse Matr3 is strongly expressed in neural crest, developing heart and great vessels, whereas Ahdc1 is not. To further establish MATR3 3' UTR disruption as the cause of the proband's LVOT defects, we prepared a mouse Matr3(Gt-ex13) gene trap allele that disrupted the 3' portion of the gene. Matr3(Gt-ex13) homozygotes are early embryo lethal, but Matr3(Gt-ex13) heterozygotes exhibit incompletely penetrant BAV, CoA and PDA phenotypes similar to those in the human proband, as well as ventricular septal defect (VSD) and double-outlet right ventricle (DORV). Both the human MATR3 translocation breakpoint and the mouse Matr3(Gt-ex13) gene trap insertion disturb the polyadenylation of MATR3 transcripts and alter Matrin 3 protein expression, quantitatively or qualitatively. Thus, subtle perturbations in Matrin 3 expression appear to cause similar LVOT defects in human and mouse.
authors.affiliation: Molecular Neurogenetics Unit and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Quintero-Rivera
authors.affiliation: Division of Genetics, Department of Medicine.
authors.forename: Qiongchao J
authors.initials: QJ
authors.lastname: Xi
authors.affiliation: Division of Medical Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Keppler-Noreuil
authors.affiliation: Molecular Neurogenetics Unit and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Anne W
authors.initials: AW
authors.lastname: Higgins
authors.affiliation: Division of Genetics, Department of Medicine, Department of Obstetrics, Gynecology and Reproductive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Anchan
authors.affiliation: Department of Cardiology, Division of Genetics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Roberts
authors.affiliation: Molecular Neurogenetics Unit and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
authors.affiliation: Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA, USA.
authors.forename: Xueping
authors.initials: X
authors.lastname: Fan
authors.affiliation: Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, USA.
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.affiliation: Division of Genetics, Department of Medicine.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Lu
authors.affiliation: Division of Genetics, Department of Medicine.
authors.forename: Joanna
authors.initials: J
authors.lastname: Tao
authors.affiliation: Division of Genetics, Department of Medicine.
authors.forename: Xuchen
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Biological Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Berezney
authors.affiliation: Mindich Child Health and Development Institute, Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.affiliation: Departments of Pediatrics and Pathology, University of Chicago, Chicago, IL, USA and.
authors.forename: Anna
authors.initials: A
authors.lastname: Kamp
authors.affiliation: Departments of Pediatrics and Pathology, University of Chicago, Chicago, IL, USA and.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
authors.affiliation: Department of Cardiology.
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Lacro
authors.affiliation: Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA, USA.
authors.forename: Weining
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.affiliation: Molecular Neurogenetics Unit and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, gusella@helix.mgh.harvard.edu maas@genetics.med.harvard.edu.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Division of Genetics, Department of Medicine, gusella@helix.mgh.harvard.edu maas@genetics.med.harvard.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
mesh_terms: D000293:Adolescent; D000818:Animals; D001017:Aortic Coarctation / Q000235:genetics* / Q000378:metabolism; D001021:Aortic Valve / Q000002:abnormalities* / Q000378:metabolism; D000082882:Bicuspid Aortic Valve Disease; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004374:Ductus Arteriosus, Patent / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006349:Heart Valve Diseases / Q000235:genetics* / Q000378:metabolism; D006352:Heart Ventricles / Q000002:abnormalities / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D016254:Mutagenesis, Insertional; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C000589131:AHDC1 protein, human; D004268:DNA-Binding Proteins; C518587:MATR3 protein, human; D034521:Nuclear Matrix-Associated Proteins; D016601:RNA-Binding Proteins; C573692:matrin-3 protein, mouse