Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice.

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.

• Authors: Joe Rainger, Ellen van Beusekom, Jacqueline K Ramsay, Lisa McKie, Lihadh Al-Gazali, Rosanna Pallotta, Anita Saponari, Peter Branney, Malcolm Fisher, Harris Morrison, Louise Bicknell, Philippe Gautier, Paul Perry, Kishan Sokhi, David Sexton, Tanya M Bardakjian, Adele S Schneider, Nursel Elcioglu, Ferda Ozkinay, Rainer Koenig, Andre Mégarbané, C Nur Semerci, Ayesha Khan, Saemah Zafar, Raoul Hennekam, Sérgio B Sousa, Lina Ramos, Livia Garavelli, Andrea Superti Furga, Anita Wischmeijer, Ian J Jackson, Gabriele Gillessen-Kaesbach, Han G Brunner, Dagmar Wieczorek, Hans van Bokhoven, David R Fitzpatrick
• Journal: PLoS genetics (PLoS Genet) Vol. 7 Issue 7 Pg. e1002114 (Jul 2011) ISSN: 1553-7404 [Electronic] United States
• PMID: 21750680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Osteonectin
• SMOC-1 protein, mouse
• SMOC1 protein, human
• BMP1 protein, human
• Bmp1 protein, mouse
• Bone Morphogenetic Protein 1

Topics

• Animals
• Anophthalmos (genetics)
• Bone Morphogenetic Protein 1 (antagonists & inhibitors, genetics)
• Coloboma (genetics)
• DNA Mutational Analysis
• Extremities (growth & development)
• Eye (growth & development)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Animal
• Mutation
• Osteonectin (genetics, metabolism)
• Pedigree
• Syndactyly (genetics)
• Waardenburg Syndrome (genetics)
• Xenopus laevis