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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Disruption of the Podosome Adaptor Protein TKS4 (SH3PXD2B) Causes the Skeletal Dysplasia, Eye, and Cardiac Abnormalities of Frank-Ter Haar Syndrome
American Journal of Human Genetics, Volume 86, No. 2, Year 2010
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Description
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. © 2010 The American Society of Human Genetics.
Authors & Co-Authors
Iqbal, Zafar
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Cejudo-Martin, Pilar
United States, San Diego
Sanford Burnham Prebys Medical Discovery Institute
de Brouwer, Arjan P.M.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
van der Zwaag, Bert
Netherlands, Utrecht
University Medical Center Utrecht
Ruiz-Lozano, Pilar
United States, San Diego
Sanford Burnham Prebys Medical Discovery Institute
Scimia, M. Cecilia
United States, San Diego
Sanford Burnham Prebys Medical Discovery Institute
Lindsey, James D.
United States, La Jolla
University of California, San Diego
Weinreb, Robert N.
United States, La Jolla
University of California, San Diego
Albrecht, Beate
Germany, Duisburg
Universität Duisburg-essen
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Alanay, Yasemin
Turkey, Ankara
Hacettepe Üniversitesi
Ben-Neriah, Ziva
Israel, Jerusalem
Hebrew University of Jerusalem
Amenduni, Mariangela
Italy, Siena
Università Degli Studi Di Siena
Artuso, Rosangela
Italy, Siena
Università Degli Studi Di Siena
Veltman, J. A.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
van Beusekom, Ellen
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Oudakker, Astrid
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Millán, José Luis San
United States, San Diego
Sanford Burnham Prebys Medical Discovery Institute
Hennekam, Raoul C.M.
Netherlands, Amsterdam
Amsterdam Umc - University of Amsterdam
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Hamel, Ben C.J.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Courtneidge, Sara A.
United States, San Diego
Sanford Burnham Prebys Medical Discovery Institute
van Bokhoven, Hans
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Statistics
Citations: 88
Authors: 22
Affiliations: 12
Identifiers
Doi:
10.1016/j.ajhg.2010.01.009
ISSN:
00029297
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Noncommunicable Diseases