title: Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model.
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.
authors.affiliation: Institute of Physiological Chemistry.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Pfirrmann
authors.affiliation: Institute of Medical and Human Genetics Development and Disease Group, Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Emmerich
authors.affiliation: Department of Ophthalmology and.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruokonen
authors.affiliation: Institute of Medical Immunology and.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Quandt
authors.affiliation: Department of Ophthalmology and.
authors.forename: Renate
authors.initials: R
authors.lastname: Buchen
authors.affiliation: Institute of Medical and Human Genetics Development and Disease Group, Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer-Zirnsak
authors.affiliation: Institute of Medical and Human Genetics Berlin-Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Institute of Medical and Human Genetics.
authors.forename: Peter
authors.initials: P
authors.lastname: Krawitz
authors.affiliation: Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Meyer
authors.affiliation: Institute of Human Genetics, Biocenter, Julius-Maximilians University Würzburg, 97074 Würzburg, Germany and.
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.affiliation: Development and Disease Group, Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany Institute for Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Hospital of Freiburg, 79106 Freiburg, Germany.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.affiliation: Institute of Medical Immunology and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.affiliation: Institute of Physiological Chemistry.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollemann
authors.affiliation: Department of Ophthalmology and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinhard
authors.affiliation: Department of Ophthalmology and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Auw-Haedrich
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Hospital of Freiburg, 79106 Freiburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.affiliation: Institute of Human Genetics, Martin Luther University Halle-Wittenberg, 06112 Halle, Saale, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, Martin Luther University Halle-Wittenberg, 06112 Halle, Saale, Germany pablo.lorini@uk-halle.de.
authors.forename: Pablo
authors.initials: P
authors.lastname: Villavicencio-Lorini
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D003315:Cornea / Q000473:pathology; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D015870:Gene Expression; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D015398:Signal Transduction; D014982:Xenopus laevis
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C486602:CHRDL1 protein, human; D005136:Eye Proteins; D009419:Nerve Tissue Proteins