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 site- and stage-specific expression during eye,limb,craniofacial,and somite development. we also report a targeted pre-conditional gene-trap mutation of smoc1 (smoc1 tm1a) 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 tm1a/tm1a). eye malformations,most commonly coloboma,and cleft palate occur in a significant proportion of smoc1 tm1a/tm1a 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. © 2011 rainger et al.