2. Academic Validation
  3. Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model

Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model

  • Hum Mol Genet. 2015 Jun 1;24(11):3119-32. doi: 10.1093/hmg/ddv063.
Thorsten Pfirrmann 1,  Denise Emmerich 2,  Peter Ruokonen 3,  Dagmar Quandt 4,  Renate Buchen 3,  Björn Fischer-Zirnsak 2,  Jochen Hecht 5,  Peter Krawitz 6,  Peter Meyer 7,  Eva Klopocki 8,  Sigmar Stricker 9,  Ekkehart Lausch 10,  Barbara Seliger 4,  Thomas Hollemann 1,  Thomas Reinhard 3,  Claudia Auw-Haedrich 3,  Bernhard Zabel 10,  Katrin Hoffmann 11,  Pablo Villavicencio-Lorini 12
Affiliations

Affiliations

  • 1 Institute of Physiological Chemistry.
  • 2 Institute of Medical and Human Genetics Development and Disease Group, Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 3 Department of Ophthalmology and.
  • 4 Institute of Medical Immunology and.
  • 5 Institute of Medical and Human Genetics Berlin-Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
  • 6 Institute of Medical and Human Genetics.
  • 7 Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland.
  • 8 Institute of Human Genetics, Biocenter, Julius-Maximilians University Würzburg, 97074 Würzburg, Germany and.
  • 9 Development and Disease Group, Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany Institute for Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
  • 10 Center for Pediatrics and Adolescent Medicine, University Hospital of Freiburg, 79106 Freiburg, Germany.
  • 11 Institute of Human Genetics, Martin Luther University Halle-Wittenberg, 06112 Halle, Saale, Germany.
  • 12 Institute of Human Genetics, Martin Luther University Halle-Wittenberg, 06112 Halle, Saale, Germany [email protected].
PMID: 25712132 DOI: 10.1093/hmg/ddv063
Abstract

Chordin-Like 1 (CHRDL1) mutations cause non-syndromic X-linked megalocornea (XMC) characterized by enlarged anterior eye segments. Mosaic corneal degeneration, presenile cataract and secondary glaucoma are associated with XMC. Beside that CHRDL1 encodes Ventroptin, a secreted bone morphogenetic protein (BMP) antagonist, the molecular mechanism of XMC is not well understood yet. In a family with broad phenotypic variability of XMC, we identified the novel CHRDL1 frameshift mutation c.807_808delTC [p.H270Wfs*22] presumably causing CHRDL1 loss of function. Using Xenopus laevis as model organism, we demonstrate that chrdl1 is specifically expressed in the ocular tissue at late developmental stages. The chrdl1 knockdown directly resembles the human XMC phenotype and confirms CHRDL1 deficiency to cause XMC. Interestingly, secondary to this bmp4 is down-regulated in the Xenopus eyes. Moreover, phospho-SMAD1/5 is altered and BMP Receptor 1A is reduced in a XMC patient. Together, we classify these observations as negative-feedback regulation due to the deficient BMP antagonism in XMC. As CHRDL1 is preferentially expressed in the limbal stem cell niche of adult human cornea, we assume that CHRDL1 plays a key role in cornea homeostasis. In conclusion, we provide novel insights into the molecular mechanism of XMC as well as into the specific role of CHRDL1 during cornea organogenesis, among Others by the establishment of the first XMC in vivo model. We show that unravelling monogenic cornea disorders like XMC-with presumably disturbed cornea growth and differentiation-contribute to the identification of potential limbal stem cell niche factors that are promising targets for regenerative therapies of corneal injuries.

Figures