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ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

Zak J 1 , Vives V 1 , Szumska D 2 , Vernet A 2 , Schneider JE 2 , Miller P 1 Show all authors , Slee EA 1 , Joss S 3 , Lacassie Y 4 , Chen E 5 , Escobar LF 6 , Tucker M 6 , Aylsworth AS 7 , Dubbs HA 8 , Collins AT 9 , Andrieux J 10 , Dieux-Coeslier A 11 , Haberlandt E 12 , Kotzot D 13 , Scott DA 14 , Parker MJ 15 , Zakaria Z 16 , Choy YS 17 , Wieczorek D 18 , Innes AM 19 , Jun KR 20 , Zinner S 9 , Prin F 21 , Lygate CA 2 , Pretorius P 22 , Rosenfeld JA 14 , Mohun TJ 21 , Lu X 1

Affiliations 

  • 1 Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK
  • 2 Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
  • 3 Queen Elizabeth University Hospital Glasgow, Glasgow G51 4TF, UK
  • 4 Department of Pediatrics, Louisiana State University, New Orleans, LA 70118, USA
  • 5 Kaiser Permanente, San Francisco Medical Center, San Francisco, CA 94115, USA
  • 6 St Vincent Children's Hospital, Indianapolis, IN 46260, USA
  • 7 Departments of Pediatrics and Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
  • 8 Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
  • 9 Seattle Children's Hospital, Seattle, WA 98105, USA
  • 10 Institute of Medical Genetics, Jeanne de Flandre Hospital, CHRU de Lille, Lille 59000, France
  • 11 CHU Lille, Clinique de Génétique, Lille F-59000, France
  • 12 Clinical Department of Pediatrics, Innsbruck Medical University, Innsbruck A-6020, Austria
  • 13 Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck A-6020, Austria
  • 14 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
  • 15 Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, S10 2TH, UK
  • 16 Institute for Medical Research, Kuala Lumpur, Jalan Pahang 50588, Malaysia
  • 17 Prince Court Medical Centre, Kuala Lumpur 50450, Malaysia
  • 18 Institute of Human Genetics, University Clinic Essen, Duisburg-Essen University, Essen 45122, Germany
  • 19 Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T3B 6A8
  • 20 Department of Laboratory Medicine, Haeundae Paik Hospital, Inje University, Haeundae-gu, Busan, Korea
  • 21 The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK
  • 22 Department of Neuroradiology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK
Cell Death Differ, 2016 Dec;23(12):1973-1984.
PMID: 27447114 DOI: 10.1038/cdd.2016.76

Abstract

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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