TY - JOUR
T1 - Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg anophthalmia) syndrome in humans and mice
AU - Rainger, Joe
AU - van Beusekom, Ellen
AU - Ramsay, Jacqueline K.
AU - McKie, Lisa
AU - Al-Gazali, Lihadh
AU - Pallotta, Rosanna
AU - Saponari, Anita
AU - Branney, Peter
AU - Fisher, Malcolm
AU - Morrison, Harris
AU - Bicknell, Louise
AU - Gautier, Philippe
AU - Perry, Paul
AU - Sokhi, Kishan
AU - Sexton, David
AU - Bardakjian, Tanya M.
AU - Schneider, Adele S.
AU - Elcioglu, Nursel
AU - Ozkinay, Ferda
AU - Koenig, Rainer
AU - Mégarbané, Andre
AU - Semerci, C. Nur
AU - Khan, Ayesha
AU - Zafar, Saemah
AU - Hennekam, Raoul
AU - Sousa, Sérgio B.
AU - Ramos, Lina
AU - Garavelli, Livia
AU - Furga, Andrea Superti
AU - Wischmeijer, Anita
AU - Jackson, Ian J.
AU - Gillessen-Kaesbach, Gabriele
AU - Brunner, Han G.
AU - Wieczorek, Dagmar
AU - van Bokhoven, Hans
AU - FitzPatrick, David R.
PY - 2011/7/1
Y1 - 2011/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960938476&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002114
DO - 10.1371/journal.pgen.1002114
M3 - Journal articles
C2 - 21750680
AN - SCOPUS:79960938476
SN - 1553-7390
VL - 7
JO - PLoS Genetics
JF - PLoS Genetics
IS - 7
M1 - e1002114
ER -