2. Academic Validation
  3. Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice

  • Hum Mol Genet. 2020 Dec 4;29(22):3662-3678. doi: 10.1093/hmg/ddaa258.
Ella M M A Martin 1,  Annabelle Enriquez 1 2,  Duncan B Sparrow 1 3 4,  David T Humphreys 2 5,  Aideen M McInerney-Leo 6,  Paul J Leo 7,  Emma L Duncan 7 8 9,  Kavitha R Iyer 1,  Joelene A Greasby 1,  Eddie Ip 2 10,  Eleni Giannoulatou 2 10,  Delicia Sheng 1,  Elizabeth Wohler 11,  Clémantine Dimartino 12 13,  Jeanne Amiel 12 13 14,  Yline Capri 15,  Daphné Lehalle 16,  Adi Mory 17,  Yael Wilnai 17,  Yael Lebenthal 18 19,  Ali G Gharavi 20,  Grażyna G Krzemień 21,  Monika Miklaszewska 22,  Robert D Steiner 23 24,  Cathy Raggio 25,  Robert Blank 26,  Hagit Baris Feldman 17 18,  Hila Milo Rasouly 20,  Nara L M Sobreira 11,  Rebekah Jobling 27,  Christopher T Gordon 12 13,  Philip F Giampietro 28,  Sally L Dunwoodie 1 2 3,  Gavin Chapman 1 2
Affiliations

Affiliations

  • 1 Development & Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney 2010, Australia.
  • 2 Faculty of Medicine, UNSW, Sydney 2052, Australia.
  • 3 Faculty of Science, UNSW, Sydney 2052, Australia.
  • 4 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
  • 5 Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Sydney 2010, Australia.
  • 6 Dermatology Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane 4072, Australia.
  • 7 Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba 4102, Australia.
  • 8 Department of Twin Research & Genetic Epidemiology, Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, London SE1 7EH, UK.
  • 9 Faculty of Medicine, University of Queensland, Herston 4006, Australia.
  • 10 Computational Genomics Laboratory, Victor Chang Cardiac Research Institute, Sydney 2010, Australia.
  • 11 McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore 21287, USA.
  • 12 Laboratory of Embryology and Genetics of Human Malformations, Institute National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris 75015, France.
  • 13 Paris Descartes-Sorbonne Paris Cité Université, Institut Imagine, Paris 75015, France.
  • 14 Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris 75015, France.
  • 15 Département de Génétique, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris 75019, France.
  • 16 Centre Hospitalier Intercommunal Créteil, Créteil 94000, France.
  • 17 The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel.
  • 18 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
  • 19 Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Pediatric Endocrinology and Diabetes Unit, Tel Aviv 6423906, Israel.
  • 20 Department of Medicine, Division of Nephrology, Columbia University, New York, NY 10032, USA.
  • 21 Department of Pediatrics and Nephrology, Warsaw Medical University, Warsaw 02-091, Poland.
  • 22 Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Kraków 30-663, Poland.
  • 23 Marshfield Clinic Health System, Marshfield, WI 54449, USA.
  • 24 University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
  • 25 Hospital for Special Surgery, Pediatrics Orthopedic Surgery, New York, NY 10021, USA.
  • 26 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • 27 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G1X3, Canada.
  • 28 Department of Pediatrics, University of Illinois-Chicago, Chicago, IL 60607, USA.
PMID: 33276377 DOI: 10.1093/hmg/ddaa258
Abstract

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

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