title: ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: J
authors.initials: J
authors.lastname: Zak
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: V
authors.initials: V
authors.lastname: Vives
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: D
authors.initials: D
authors.lastname: Szumska
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: A
authors.initials: A
authors.lastname: Vernet
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Schneider
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: P
authors.initials: P
authors.lastname: Miller
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Slee
authors.affiliation: Queen Elizabeth University Hospital Glasgow, Glasgow G51 4TF, UK.
authors.forename: S
authors.initials: S
authors.lastname: Joss
authors.affiliation: Department of Pediatrics, Louisiana State University, New Orleans, LA 70118, USA.|Genetics Services, Children's Hospital New Orleans, New Orleans, LA 70118, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lacassie
authors.affiliation: Kaiser Permanente, San Francisco Medical Center, San Francisco, CA 94115, USA.
authors.forename: E
authors.initials: E
authors.lastname: Chen
authors.affiliation: St Vincent Children's Hospital, Indianapolis, IN 46260, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Escobar
authors.affiliation: St Vincent Children's Hospital, Indianapolis, IN 46260, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tucker
authors.affiliation: Departments of Pediatrics and Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Aylsworth
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Dubbs
authors.affiliation: Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Collins
authors.affiliation: Institute of Medical Genetics, Jeanne de Flandre Hospital, CHRU de Lille, Lille 59000, France.
authors.forename: J
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: CHU Lille, Clinique de Génétique, Lille F-59000, France.
authors.forename: A
authors.initials: A
authors.lastname: Dieux-Coeslier
authors.affiliation: Clinical Department of Pediatrics, Innsbruck Medical University, Innsbruck A-6020, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Haberlandt
authors.affiliation: Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck A-6020, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Kotzot
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, S10 2TH, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: Institute for Medical Research, Kuala Lumpur, Jalan Pahang 50588, Malaysia.
authors.forename: Z
authors.initials: Z
authors.lastname: Zakaria
authors.affiliation: Prince Court Medical Centre, Kuala Lumpur 50450, Malaysia.
authors.forename: Y S
authors.initials: YS
authors.lastname: Choy
authors.affiliation: Institute of Human Genetics, University Clinic Essen, Duisburg-Essen University, Essen 45122, Germany.|Institute of Human Genetics, University Clinic, Heinrich-Heine University, Düsseldorf 40225, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T3B 6A8.
authors.forename: A M
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Laboratory Medicine, Haeundae Paik Hospital, Inje University, Haeundae-gu, Busan, Korea.
authors.forename: K R
authors.initials: KR
authors.lastname: Jun
authors.affiliation: Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: S
authors.initials: S
authors.lastname: Zinner
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.
authors.forename: F
authors.initials: F
authors.lastname: Prin
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Lygate
authors.affiliation: Department of Neuroradiology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK.
authors.forename: P
authors.initials: P
authors.lastname: Pretorius
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Mohun
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: X
authors.initials: X
authors.lastname: Lu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000378:metabolism; D001921:Brain / Q000002:abnormalities / Q000473:pathology; D002872:Chromosome Deletion; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006352:Heart Ventricles / Q000002:abnormalities / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009436:Neural Tube Defects / Q000473:pathology; D010641:Phenotype; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C090468:TP53BP2 protein, human; C511437:Trp53bp2 protein, mouse; D025521:Tumor Suppressor Proteins