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

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

Anophthalmia-Waardenburg syndrome: A report of three cases

We report on 2 Turkish families with children who had bilateral anophthalmia, upper and lower limb abnormalities, mental retardation and consanguineous parents, We have evaluated the 2 cases in the first family and the only case in the second as anophthalmia-Waardenburg syndrome, This is an extremely rare autosomal recessive syndrome. (C) 1996 Wiley-Liss, Inc

A family presenting Goltz syndrome (focal dermal hypoplasia) in three generations

In this report we present three affected females of the same family in three generations. The cases have features of focal dermal hypoplasia (Goltz syndrome), One of the three affected females is the index case and the others are her mother and her grandmother. We performed skin biopsies on them. According to histopathological examinations skin lesions were compatible with Goltz syndrome. These cases exhibited focal dermal hypoplasia (FDH) manifestations including skin, dental and skeletal abnormalities. The affected females were seen in three generations of the same family which pointed to its X-linked dominance

Osteoporosis-Pseudoglioma Syndrome: Three Novel Mutations in the LRP5 Gene and Response to Bisphosphonate Treatment

Background/Aims: Osteoporosis-pseudoglioma (OPPG) syndrome is a rare disorder characterized by congenital or infancy-onset visual loss and severe juvenile osteoporosis. OPPG is caused by homozygous mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. We present three novel homozygous LRP5 mutations found in 3 unrelated Turkish children with consanguineous parents, along with clinical phenotypes and response to treatment with bisphosphonates (bisP). Methods/Results: The LRP5 gene was analyzed by direct sequencing after PCR amplification. Mutation screening for LRP5 revealed homozygous nonsense R1002X mutation in the first patient and homozygous missense mutations V336M and G507S in the second and third patient, respectively. The parents were heterozygous for these mutations. The patients' eye symptoms began during the first months of life but the OPPG diagnoses were made based on skeletal deformities and osteopenia after 4 years of age. The patients' bone mineral density Z scores were very low and consistent with osteopenia. All patients were treated with bisP for 3.5-7 years. Conclusion: We report three novel LRP5 mutations in 3 Turkish patients with OPPG. We show that the response of bisP therapy has improved the lumbar spinal bone mineral density Z scores and the patients' quality of life as the bone pains decreased. Copyright (C) 2012 S. Karger AG, Base