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XB-ART-43515
PLoS Genet July 1, 2011; 7 (7): e1002114.
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Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice.

Rainger J , van Beusekom E , Ramsay JK , McKie L , Al-Gazali L , Pallotta R , Saponari A , Branney P , Fisher M , Morrison H , Bicknell L , Gautier P , Perry P , Sokhi K , Sexton D , Bardakjian TM , Schneider AS , Elcioglu N , Ozkinay F , Koenig R , Mégarbané A , Semerci CN , Khan A , Zafar S , Hennekam R , Sousa SB , Ramos L , Garavelli L , Furga AS , Wischmeijer A , Jackson IJ , Gillessen-Kaesbach G , Brunner HG , Wieczorek D , van Bokhoven H , Fitzpatrick DR .


Abstract
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.

PubMed ID: 21750680
PMC ID: PMC3131273
Article link: PLoS Genet
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: gal.2 npat rpe smoc1


Article Images: [+] show captions
References [+] :
Abouzeid, Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome. 2011, Pubmed