Disruption of the Podosome Adaptor Protein TKS4 (SH3PXD2B) Causes the Skeletal Dysplasia, Eye, and Cardiac Abnormalities of Frank-Ter Haar Syndrome

Zafar Iqbal, Pilar Cejudo-Martin, Arjan de Brouwer, Bert van der Zwaag, Pilar Ruiz-Lozano, M. Cecilia Scimia, James D. Lindsey, Robert Weinreb, Beate Albrecht, Andre Megarbane, Yasemin Alanay, Ziva Ben-Neriah, Mariangela Amenduni, Rosangela Artuso, Joris A. Veltman, Ellen van Beusekom, Astrid Oudakker, José Luis Millán, Raoul Hennekam, Ben HamelSara Courtneidge, Hans van Bokhoven

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)254-261
Number of pages8
JournalAmerican Journal of Human Genetics
Volume86
Issue number2
DOIs
StatePublished - Feb 12 2010
Externally publishedYes

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Eye Abnormalities
Proteins
Mutation
Cardiovascular Abnormalities
Hypertelorism
src Homology Domains
Genetic Heterogeneity
Ter Haar syndrome
Podosomes
Intraocular Pressure
Causality
Proteolysis
Genes
Embryonic Development
Cell Movement
Actins
Fibroblasts
Chromosomes
Skin
Membranes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Disruption of the Podosome Adaptor Protein TKS4 (SH3PXD2B) Causes the Skeletal Dysplasia, Eye, and Cardiac Abnormalities of Frank-Ter Haar Syndrome. / Iqbal, Zafar; Cejudo-Martin, Pilar; de Brouwer, Arjan; van der Zwaag, Bert; Ruiz-Lozano, Pilar; Scimia, M. Cecilia; Lindsey, James D.; Weinreb, Robert; Albrecht, Beate; Megarbane, Andre; Alanay, Yasemin; Ben-Neriah, Ziva; Amenduni, Mariangela; Artuso, Rosangela; Veltman, Joris A.; van Beusekom, Ellen; Oudakker, Astrid; Millán, José Luis; Hennekam, Raoul; Hamel, Ben; Courtneidge, Sara; van Bokhoven, Hans.

In: American Journal of Human Genetics, Vol. 86, No. 2, 12.02.2010, p. 254-261.

Research output: Contribution to journalArticle

Iqbal, Z, Cejudo-Martin, P, de Brouwer, A, van der Zwaag, B, Ruiz-Lozano, P, Scimia, MC, Lindsey, JD, Weinreb, R, Albrecht, B, Megarbane, A, Alanay, Y, Ben-Neriah, Z, Amenduni, M, Artuso, R, Veltman, JA, van Beusekom, E, Oudakker, A, Millán, JL, Hennekam, R, Hamel, B, Courtneidge, S & van Bokhoven, H 2010, '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, vol. 86, no. 2, pp. 254-261. https://doi.org/10.1016/j.ajhg.2010.01.009
Iqbal, Zafar ; Cejudo-Martin, Pilar ; de Brouwer, Arjan ; van der Zwaag, Bert ; Ruiz-Lozano, Pilar ; Scimia, M. Cecilia ; Lindsey, James D. ; Weinreb, Robert ; Albrecht, Beate ; Megarbane, Andre ; Alanay, Yasemin ; Ben-Neriah, Ziva ; Amenduni, Mariangela ; Artuso, Rosangela ; Veltman, Joris A. ; van Beusekom, Ellen ; Oudakker, Astrid ; Millán, José Luis ; Hennekam, Raoul ; Hamel, Ben ; Courtneidge, Sara ; van Bokhoven, Hans. / Disruption of the Podosome Adaptor Protein TKS4 (SH3PXD2B) Causes the Skeletal Dysplasia, Eye, and Cardiac Abnormalities of Frank-Ter Haar Syndrome. In: American Journal of Human Genetics. 2010 ; Vol. 86, No. 2. pp. 254-261.
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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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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

AU - van Bokhoven, Hans

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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.

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