title: 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.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Rainger
authors.forename: Ellen
authors.initials: E
authors.lastname: van Beusekom
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Ramsay
authors.forename: Lisa
authors.initials: L
authors.lastname: McKie
authors.forename: Lihadh
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authors.lastname: Al-Gazali
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pallotta
authors.forename: Anita
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authors.lastname: Saponari
authors.forename: Peter
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authors.lastname: Branney
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authors.lastname: Fisher
authors.forename: Harris
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authors.lastname: Morrison
authors.forename: Louise
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authors.lastname: Bicknell
authors.forename: Philippe
authors.initials: P
authors.lastname: Gautier
authors.forename: Paul
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authors.forename: Kishan
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authors.lastname: Sokhi
authors.forename: David
authors.initials: D
authors.lastname: Sexton
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Bardakjian
authors.forename: Adele S
authors.initials: AS
authors.lastname: Schneider
authors.forename: Nursel
authors.initials: N
authors.lastname: Elcioglu
authors.forename: Ferda
authors.initials: F
authors.lastname: Ozkinay
authors.forename: Rainer
authors.initials: R
authors.lastname: Koenig
authors.forename: Andre
authors.initials: A
authors.lastname: Mégarbané
authors.forename: C Nur
authors.initials: CN
authors.lastname: Semerci
authors.forename: Ayesha
authors.initials: A
authors.lastname: Khan
authors.forename: Saemah
authors.initials: S
authors.lastname: Zafar
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Sérgio B
authors.initials: SB
authors.lastname: Sousa
authors.forename: Lina
authors.initials: L
authors.lastname: Ramos
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.forename: Andrea Superti
authors.initials: AS
authors.lastname: Furga
authors.forename: Anita
authors.initials: A
authors.lastname: Wischmeijer
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: David R
authors.initials: DR
authors.lastname: Fitzpatrick
mesh_terms: D000818:Animals; D000853:Anophthalmos / Q000235:genetics*; D055395:Bone Morphogenetic Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D003103:Coloboma / Q000235:genetics; D004252:DNA Mutational Analysis; D005121:Extremities / Q000254:growth & development; D005123:Eye / Q000254:growth & development; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D013576:Syndactyly / Q000235:genetics; D014849:Waardenburg Syndrome / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: D015676:Osteonectin; C524549:SMOC-1 protein, mouse; C468135:SMOC1 protein, human; C525705:BMP1 protein, human; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1