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Disruption of the Podosome Adaptor Protein TKS4 (SH3PXD2B) Causes the Skeletal Dysplasia, Eye, and Cardiac Abnormalities of Frank-Ter Haar Syndrome |
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| Authors: | Zafar Iqbal,Pilar Cejudo-Martin,Arjan de Brouwer,Pilar Ruiz-Lozano,James D. Lindsey,Beate Albrecht,Yasemin Alanay,Mariangela Amenduni,Joris A. Veltman,Astrid Oudakker,José Luis Millá n,Ben Hamel,Hans van Bokhoven |
| Affiliation: | 1 Department of Human Genetics 855, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands 2 Department of Cognitive Neurosciences 126, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands 3 Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA 4 Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands 5 Hamilton Glaucoma Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA 6 Institut für Humangenetik, Universitätsklinikum, Universität Duisburg-Essen, 45122 Essen, Germany 7 Medical Genetics Unit, Saint Joseph University, 1107 2180 Beirut, Lebanon 8 Pediatric Genetics Unit, Department of Pediatrics, Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey 9 Center for Human Genetics, Hadassah Medical Center, Hebrew University of Jerusalem, 91120 Jerusalem, Israel 10 Medical Genetics, Department of Molecular Biology, University of Siena, Policlinico Le Scotte, viale Bracci 2, 53100 Siena, Italy 11 Department of Pediatrics, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands 12 Institute of Child Health, Great Ormond Street Hospital for Children, University College London, London WC1N 1 EH, UK |
| Abstract: | Frank-Ter Haar syndrome (FTHS), also known as Ter Haar syndrome, is an autosomal-recessive disorder characterized by skeletal, cardiovascular, and eye abnormalities, such as increased intraocular pressure, prominent eyes, and hypertelorism. We have conducted homozygosity mapping on patients representing 12 FTHS families. A locus on chromosome 5q35.1 was identified for which patients from nine families shared homozygosity. For one family, a homozygous deletion mapped exactly to the smallest region of overlapping homozygosity, which contains a single gene, SH3PXD2B. This gene encodes the TKS4 protein, a phox homology (PX) and Src homology 3 (SH3) domain-containing adaptor protein and Src substrate. This protein was recently shown to be involved in the formation of actin-rich membrane protrusions called podosomes or invadopodia, which coordinate pericellular proteolysis with cell migration. Mice lacking Tks4 also showed pronounced skeletal, eye, and cardiac abnormalities and phenocopied the majority of the defects associated with FTHS. These findings establish a role for TKS4 in FTHS and embryonic development. Mutation analysis revealed five different homozygous mutations in SH3PXD2B in seven FTHS families. No SH3PXD2B mutations were detected in six other FTHS families, demonstrating the genetic heterogeneity of this condition. Interestingly however, dermal fibroblasts from one of the individuals without an SH3PXD2B mutation nevertheless expressed lower levels of the TKS4 protein, suggesting a common mechanism underlying disease causation. |
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