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.
Ophthalmo-acromelic syndrome (OAS) is a rare congenital genetic disorder involving complete absence of the eyes and limb malformations, with missing or fused bones in the feet and hands. In this paper we report the identification of genetic changes to both copies of the
SMOC1
gene as the cause of most cases of OAS. We have identified eight different mutations in this gene in unrelated individuals, and six of these mutations are predicted to completely abolish SMOC-1 function. We have also genetically disrupted the mouse
Smoc1
gene to produce only 10% of normal levels. These animals, called
Smoc1
tm1a/tm1a
mice, have similar hindlimb malformations to those seen in the limbs of human OAS patients, resulting in missing toes in some mice and fusion of toes in others.
Smoc1
tm1a/tm1a
embryos and pups also have eye malformations but these are milder than those seen in human cases, perhaps because, unlike the human cases, the mice still have some residual function of the gene. We suggest that the normal function of SMOC-1 may be to regulate an important class of growth factors, called Bone Morphogenetic Proteins (BMPs), which are essential for normal embryonic development.