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

• Published in: Human molecular genetics 2015-06, Vol.24 (11), p.3119-3132
• Main Authors: Pfirrmann, Thorsten, Emmerich, Denise, Ruokonen, Peter, Quandt, Dagmar, Buchen, Renate, Fischer-Zirnsak, Björn, Hecht, Jochen, Krawitz, Peter, Meyer, Peter, Klopocki, Eva, Stricker, Sigmar, Lausch, Ekkehart, Seliger, Barbara, Hollemann, Thomas, Reinhard, Thomas, Auw-Haedrich, Claudia, Zabel, Bernhard, Hoffmann, Katrin, Villavicencio-Lorini, Pablo
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Base Sequence; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein 4 - metabolism; Cornea - pathology; DNA Mutational Analysis; Eye Diseases, Hereditary - genetics; Eye Proteins - genetics; Female; Frameshift Mutation; Gene Expression; Genetic Association Studies; Genetic Diseases, X-Linked - genetics; Humans; Male; Nerve Tissue Proteins - genetics; Pedigree; Signal Transduction; Xenopus laevis
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv063

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.