TY - JOUR
T1 - Disruption of the Podosome Adaptor Protein TKS4 (SH3PXD2B) Causes the Skeletal Dysplasia, Eye, and Cardiac Abnormalities of Frank-Ter Haar Syndrome
AU - Iqbal, Zafar
AU - Cejudo-Martin, Pilar
AU - de Brouwer, Arjan
AU - van der Zwaag, Bert
AU - Ruiz-Lozano, Pilar
AU - Scimia, M. Cecilia
AU - Lindsey, James D.
AU - Weinreb, Robert
AU - Albrecht, Beate
AU - Megarbane, Andre
AU - Alanay, Yasemin
AU - Ben-Neriah, Ziva
AU - Amenduni, Mariangela
AU - Artuso, Rosangela
AU - Veltman, Joris A.
AU - van Beusekom, Ellen
AU - Oudakker, Astrid
AU - Millán, José Luis
AU - Hennekam, Raoul
AU - Hamel, Ben
AU - Courtneidge, Sara A.
AU - van Bokhoven, Hans
N1 - Funding Information:
We thank the families for their cooperation in this study; Hulya Kayserili (Istanbul), Helen Stewart (London), Emma Wakeling (London), Valerie Cormier-Daire (Paris), and Charles Scott Jr. (Wilmington) for providing patient material; Ehud Banne for clinical investigations in family 13; Karen X. Duong-Polk for assistance with the experiments on the mouse eyes; Saskia van der Velde-Vissers and Christel Beumer for fibroblast culture; Irene Janssen for carrying out the SNP microarray analysis; and Jeroen Bakkers and Evelyn Kouwenhoven for animal studies and scientific discussion. This research in the Courtneidge laboratory was funded by the National Cancer Institute (CA098383) and the Mathers Foundation, and by Beatriu de Pinos fellowship support (Comissionat per a Universitats I Recerca del Departament d'Innovacio, Universitats I Empresa de la Generalitat de Catalunya) to P.C.-M. P.R.-L. and J.L.M. are supported by the National Institutes of Health, and M.C.S. is a fellow of the California Institute of Regenerative Medicine. Z.I. was supported by a fellowship from the Higher Education Commission (HEC) of Pakistan. The authors declare no conflicting financial interests.
PY - 2010/2/12
Y1 - 2010/2/12
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2010.01.009
DO - 10.1016/j.ajhg.2010.01.009
M3 - Article
C2 - 20137777
AN - SCOPUS:76049088520
SN - 0002-9297
VL - 86
SP - 254
EP - 261
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -