1. Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice
- Author
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Kishan Sokhi, Jacqueline Ramsay, Tanya Bardakjian, Adele Schneider, Nursel Elcioglu, Raoul C.M. Hennekam, C. Nur Semerci, Ferda Ozkinay, Joe Rainger, David Sexton, Andrea Superti Furga, Anita Saponari, Lina Ramos, Ellen van Beusekom, Malcolm E. Fisher, Gabriele Gillessen-Kaesbach, Anita Wischmeijer, Ian J. Jackson, Sérgio B. Sousa, Hans van Bokhoven, Rainer Koenig, Lihadh Al-Gazali, Paul Perry, Peter Branney, Louise S. Bicknell, Harris Morrison, Livia Garavelli, Dagmar Wieczorek, André Mégarbané, Rosanna Pallotta, Han G. Brunner, Lisa McKie, Saemah Nuzhat Zafar, Philippe Gautier, Ayesha Khan, David R. FitzPatrick, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, Ege Üniversitesi, Rainger, Joe, van Beusekom, Ellen, Ramsay, Jacqueline K., McKie, Lisa, Al-Gazali, Lihadh, Pallotta, Rosanna, Saponari, Anita, Branney, Peter, Fisher, Malcolm, Morrison, Harris, Bicknell, Louise, Gautier, Philippe, Perry, Paul, Sokhi, Kishan, Sexton, David, Bardakjian, Tanya M., Schneider, Adele S., Elcioglu, Nursel, Ozkinay, Ferda, Koenig, Rainer, Megarbane, Andre, Semerci, C. Nur, Khan, Ayesha, Zafar, Saemah, Hennekam, Raoul, Sousa, Sergio B., Ramos, Lina, Garavelli, Livia, Furga, Andrea Superti, Wischmeijer, Anita, Jackson, Ian J., Gillessen-Kaesbach, Gabriele, Brunner, Han G., Wieczorek, Dagmar, van Bokhoven, Hans, FitzPatrick, David R., and Faculteit der Geneeskunde
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ANOMALIES ,DNA Mutational Analysis ,PROTEIN ,anophthalmia ,gene targeting ,Bone Morphogenetic Protein 1 ,hindlimb ,Mice ,Xenopus laevis ,genetic linkage ,BINDING ,genetics ,Waardenburg's Syndrome ,Waardenburg Syndrome ,clinical article ,C57BL mouse ,adult ,Mus ,microsatellite marker ,DEFECTS ,gene expression regulation ,Disease gene identification ,BMP1 protein, human ,Pedigree ,Medicine ,down regulation ,mutational analysis ,drug antagonism ,medicine.medical_specialty ,SMOC1 protein, human ,embryo ,Bone morphogenetic protein ,animal tissue ,loss of function mutation ,Smoc1 gene ,Genetics ,Humans ,human ,Biology ,Molecular Biology ,Waardenburg syndrome ,mouse ,Ecology, Evolution, Behavior and Systematics ,MUTATIONS ,animal model ,Correction ,SMOC-1 protein, mouse ,school child ,medicine.disease ,Mice, Inbred C57BL ,Human Reproduction [NCEBP 12] ,gene function ,Endocrinology ,decapentaplegic protein ,Genetics and epigenetic pathways of disease Functional Neurogenomics [NCMLS 6] ,Mutation ,Cancer Research ,frameshift mutation ,Medizin ,nonsense mutation ,Gene Expression ,mouse mutant ,Eye ,Bmp1 protein, mouse ,Autosomal Recessive ,bone morphogenetic protein ,Missense mutation ,animal ,Osteonectin ,SPECIFICATION ,Genetics (clinical) ,RECESSIVE ANOPHTHALMIA ,limb ,cleft palate ,Mice, Knockout ,child ,Coloboma ,ABNORMALITIES ,messenger RNA ,article ,pedigree ,female ,Mammalia ,Models, Animal ,Drosophila ,Research Article ,gene locus ,lcsh:QH426-470 ,Nonsense mutation ,procollagen C proteinase ,male ,ddc:570 ,Internal medicine ,medicine ,Animalia ,Animals ,gene ,SMOC 1 protein, mouse ,gene identification ,growth, development and aging ,Clinical Genetics ,Phenocopy ,nonhuman ,Anophthalmia ,missense mutation ,syndactyly ,Anophthalmos ,nucleotide sequence ,Human Genetics ,Extremities ,infant ,lcsh:Genetics ,XENOPUS ,CELL-DEATH ,adolescent ,Genetics of Disease ,Syndactyly ,homozygosity ,Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] ,metabolism ,Animal Genetics - Abstract
WOS: 000293338600004, PubMed ID: 21750680, 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 (Smoc(1tm1a)) that reduces mRNA to similar to 10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc(1tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc(1tm1a/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., Medical Research Council (UK)Medical Research Council UK (MRC); Medical Research CouncilMedical Research Council UK (MRC) [MC_U127561093, MC_PC_U127561112, MC_U127561112], 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.
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- 2011