Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice

Joe Rainger,Anita Saponari,Sérgio B Sousa,Philippe Gautier,Livia Garavelli,Anita Wischmeijer,Ian J Jackson,Lisa Mckie,Hans Van Bokhoven,Ellen Van Beusekom,Dagmar Wieczorek,Paul Perry,David Sexton,Han G Brunner,Ayesha Khan,Andrea Superti Furga,C Nur Semerci,Peter Branney,Harris Morrison,Malcolm Fisher,Kishan Sokhi,David R Fitzpatrick,Rainer Koenig,Lihadh Al‐Gazali ,Raoul C M Hennekam ,André Megarbane ,Saemah Nuzhat Zafar ,Leonor Ramos ,Tanya Bardakjian ,Gabriele Gillessen‐Kaesbach ,Nursel Elcioğlu ,Adele Schneider ,Ferda Özkınay ,R Pallotta ,Jacqueline Ramsay ,Louise S Bicknell

doi:10.1371/journal.pgen.1002114

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 (Smoc1tm1a) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1tm1a/tm1a). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1tm1a/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.

Highlights

IntroductionCongenital absence of an eye (here termed anophthalmia) is a rare malformation in humans with a live birth prevalence of less than 1 in 10,000 [1]
Congenital absence of an eye is a rare malformation in humans with a live birth prevalence of less than 1 in 10,000 [1]
In this paper we report the identification of genetic changes to both copies of the SMOC1 gene as the cause of most cases of Ophthalmo-acromelic syndrome (OAS)

Summary

Introduction

Congenital absence of an eye (here termed anophthalmia) is a rare malformation in humans with a live birth prevalence of less than 1 in 10,000 [1]. Identifiable single gene disorders account for ,25% of bilateral anophthalmia. The known genetic causes include compound heterozygous mutations in PAX6, de novo heterozygous loss-of-function mutations in SOX2 [2,3,4], inherited or de novo heterozygous loss-of-function mutations in OTX2 [5,6], homozygous loss-of-function mutations in STRA6 [7] and possibly inherited, heterozygous loss-of-function mutations in BMP4 [8]. In most cases of anophthalmia no eye is visible on clinical

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