VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5

  1. Dorota Szumska1,10,
  2. Guido Pieles1,10,
  3. Rachid Essalmani2,
  4. Michal Bilski1,
  5. Daniel Mesnard3,
  6. Kulvinder Kaur4,
  7. Angela Franklyn1,
  8. Kamel El Omari4,
  9. Joanna Jefferis1,
  10. Jamie Bentham1,
  11. Jennifer M. Taylor4,
  12. Jurgen E. Schneider1,
  13. Sebastian J. Arnold4,
  14. Paul Johnson5,
  15. Zuzanna Tymowska-Lalanne6,
  16. Dave Stammers4,
  17. Kieran Clarke7,
  18. Stefan Neubauer1,
  19. Andrew Morris4,
  20. Steve D. Brown6,
  21. Charles Shaw-Smith8,
  22. Armando Cama9,
  23. Valeria Capra9,
  24. Jiannis Ragoussis4,
  25. Daniel Constam3,
  26. Nabil G. Seidah2,
  27. Annik Prat2, and
  28. Shoumo Bhattacharya1,11
  1. 1 Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
  2. 2 Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada;
  3. 3 Swiss Institute for Experimental Cancer Research-École Polytechnique Fédérale de Lausanne (ISREC-EPFL), Swiss Federal Institute of Technology, CH-1066 Epalinges, Lausanne, Switzerland;
  4. 4 Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom;
  5. 5 Nuffield Department of Surgery, University of Oxford, Oxford OX3 9DU, United Kingdom;
  6. 6 Medical Research Council (MRC) Mammalian Genetics Unit, Harwell OX11 0RD, United Kingdom;
  7. 7 Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
  8. 8 Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge CB2 0XY, United Kingdom;
  9. 9 Unitá Operativa Neurochirurgia, Istituto G. Gaslini, 16148 Genova, Italy
  1. 10 These authors contributed equally to this work.

Abstract

We have identified an ethylnitrosourea (ENU)-induced recessive mouse mutation (Vcc) with a pleiotropic phenotype that includes cardiac, tracheoesophageal, anorectal, anteroposterior patterning defects, exomphalos, hindlimb hypoplasia, a presacral mass, renal and palatal agenesis, and pulmonary hypoplasia. It results from a C470R mutation in the proprotein convertase PCSK5 (PC5/6). Compound mutants (Pcsk5Vcc/null) completely recapitulate the Pcsk5Vcc/Vcc phenotype, as does an epiblast-specific conditional deletion of Pcsk5. The C470R mutation ablates a disulfide bond in the P domain, and blocks export from the endoplasmic reticulum and proprotein convertase activity. We show that GDF11 is cleaved and activated by PCSK5A, but not by PCSK5A-C470R, and that Gdf11-deficient embryos, in addition to having anteroposterior patterning defects and renal and palatal agenesis, also have a presacral mass, anorectal malformation, and exomphalos. Pcsk5 mutation results in abnormal expression of several paralogous Hox genes (Hoxa, Hoxc, and Hoxd), and of Mnx1 (Hlxb9). These include known Gdf11 targets, and are necessary for caudal embryo development. We identified nonsynonymous mutations in PCSK5 in patients with VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, limb malformation OMIM 192350) and caudal regression syndrome, the phenotypic features of which resemble the mouse mutation. We propose that Pcsk5, at least in part via GDF11, coordinately regulates caudal Hox paralogs, to control anteroposterior patterning, nephrogenesis, skeletal, and anorectal development.

Keywords

Footnotes

  • 11 Corresponding author.

    11 E-MAIL shoumo.bhattacharya{at}well.ox.ac.uk; FAX 44-1865-287742.

  • Supplemental material is available at http://www.genesdev.org.

  • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.479408.

    • Received March 12, 2008.
    • Accepted April 1, 2008.
  • Freely available online through the Genes & Development Open Access option.

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