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

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.

Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome

“…Glaucoma was absent in individuals with BDCS and was also absent in three of seven individuals with FTHS owing to complete loss of SH3PXD2B. 17 Figure 3 Molecular characterization of SH3PXD2B. PCR analysis of genomic DNA spanning exon 12, the coding region of exon 13, the 3 0 UTR and a downstream intronic region of SH3PXD2B in BDCS3-affected patients (BDCS3-3, BDCS3-4) confirmed the deletion of exon 13.…”

“…17 FTHS is a progressive autosomal recessive condition displaying several clinical features directly comparable to those observed in BDCS including the craniofacial anomalies, skeletal dysplasia and cardiac defects. 17,[19][20][21][22][23][24] However, some phenotypic traits differ between the described syndromes, perhaps explaining why only a single report has speculated that the two syndromes might represent a single clinical entity. 21 For example, eye abnormalities such as megalocornea are commonly observed in both SH3PXD2B-mediated FTHS and Sh3pxd2b null mice where deletion or frameshift mutation results in the complete loss of SH3PXD2B.…”

“…Sh3pxd2b null mice replicate many of the clinical features of BDCS, including severe craniofacial and skeletal deformities such as hypertelorism and kyphosis and ventricular and mitral valve defects. 17,18 Interestingly, SH3PXD2B missense and frameshift mutations have been recently shown to underlie approximately 50% (7/13 families analyzed) of patients with Frank-Ter Haar Syndrome (FTHS, (MIM249420)). 17 FTHS is a progressive autosomal recessive condition displaying several clinical features directly comparable to those observed in BDCS including the craniofacial anomalies, skeletal dysplasia and cardiac defects.…”

“…17,18 Interestingly, SH3PXD2B missense and frameshift mutations have been recently shown to underlie approximately 50% (7/13 families analyzed) of patients with Frank-Ter Haar Syndrome (FTHS, (MIM249420)). 17 FTHS is a progressive autosomal recessive condition displaying several clinical features directly comparable to those observed in BDCS including the craniofacial anomalies, skeletal dysplasia and cardiac defects. 17,[19][20][21][22][23][24] However, some phenotypic traits differ between the described syndromes, perhaps explaining why only a single report has speculated that the two syndromes might represent a single clinical entity.…”

“…21 For example, eye abnormalities such as megalocornea are commonly observed in both SH3PXD2B-mediated FTHS and Sh3pxd2b null mice where deletion or frameshift mutation results in the complete loss of SH3PXD2B. 17,25 In contrast, eye anomalies have either not been observed or not been reported in patients with BDCS. Glaucoma was absent in individuals with BDCS and was also absent in three of seven individuals with FTHS owing to complete loss of SH3PXD2B.…”