UvA-DARE ( Digital Academic Repository ) Loss of the BMP Antagonist , SMOC-1 , Causes Ophthalmo-Acromelic ( Waardenburg Anophthalmia ) Syndrome in Humans and Mice

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows siteand stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1) that reduces mRNA to ,10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1 embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice. Citation: Rainger J, van Beusekom E, Ramsay JK, McKie L, Al-Gazali L, et al. (2011) Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice. PLoS Genet 7(7): e1002114. doi:10.1371/journal.pgen.1002114 Editor: Andrew O. M. Wilkie, University of Oxford, United Kingdom Received December 29, 2010; Accepted April 15, 2011; Published July 7, 2011 Copyright: 2011 Rainger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Funding for this project was provided as an intramural program grant from the Medical Research Council (UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: david.fitzpatrick@hgu.mrc.ac.uk (DRF); H.vanBokhoven@antrg.umcn.nl (HvB)