A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum

Durand, Benjamin; Schaefer, Eric; Calmels, Nadège; Scheidecker, Sophie; Kempf, Nadine; Melo, Charlie De; Guilbert, Anne-Sophie; Timbolschi, Dana; Donato, L.; Astruc, Dominique; Sauer, Arnaud; Antal, Maria Cristina; Dollfus, Hélène; Chehadeh, Salima El

doi:10.1016/j.ejmg.2020.103857

Cited by 14 publications

(15 citation statements)

References 23 publications

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“…Genome analysis of FTHS patient samples uncovered several major mutations in the TKS4 region, including mutations in the PX domain and between the second and third SH3 domains as well as an extensive deletion from exon 13 that leads to a truncated TKS4 protein/gene product with only two SH3 domains (Figure 4a) [164,165,183,184]. Early stop codon-introducing homozygous mutations (c.147insT or F49X) or a deletion (c.969delG), which lead to the expression of truncated TKS4 1-48 and TKS4 1-341 mutant proteins, respectively, were detected in some FTHS-affected families (Figure 4a) [164,185]. In transfected cells, the truncated mutant TKS4 protein showed no expression, while TKS4 abnormally accumulated in the nucleus, suggesting that these mutations result in dysfunctional TKS4 proteins that could lead to FTHS [5].…”

Section: Pathological Conditions Related To Tks Protein Dysfunctionmentioning

confidence: 99%

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Kudlik

Takács

Radnai

et al. 2020

IJMS

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Scaffold proteins are typically thought of as multi-domain “bridging molecules.” They serve as crucial regulators of key signaling events by simultaneously binding multiple participants involved in specific signaling pathways. In the case of epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) binding, the activated EGFR contacts cytosolic SRC tyrosine-kinase, which then becomes activated. This process leads to the phosphorylation of SRC-substrates, including the tyrosine kinase substrates (TKS) scaffold proteins. The TKS proteins serve as a platform for the recruitment of key players in EGFR signal transduction, promoting cell spreading and migration. The TKS4 and the TKS5 scaffold proteins are tyrosine kinase substrates with four or five SH3 domains, respectively. Their structural features allow them to recruit and bind a variety of signaling proteins and to anchor them to the cytoplasmic surface of the cell membrane. Until recently, TKS4 and TKS5 had been recognized for their involvement in cellular motility, reactive oxygen species-dependent processes, and embryonic development, among others. However, a number of novel functions have been discovered for these molecules in recent years. In this review, we attempt to cover the diverse nature of the TKS molecules by discussing their structure, regulation by SRC kinase, relevant signaling pathways, and interaction partners, as well as their involvement in cellular processes, including migration, invasion, differentiation, and adipose tissue and bone homeostasis. We also describe related pathologies and the established mouse models.

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Section: Pathological Conditions Related To Tks Protein Dysfunctionmentioning

confidence: 99%

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Kudlik

Takács

Radnai

et al. 2020

IJMS

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“…Table 2 summarizes all SH3PXD2B variants reported to be associated with the FTHS phenotype. The primary phenotypic characteristics of FTHS are skeletal, cardiovascular, ocular, and craniofacial anomalies, including brachycephaly, hypertelorism, anterior fontanelle, and developmental delay [ 1 , 2 ]. In this study, many of the index patient’s clinical features and symptoms aligned with FTHS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Frank–Ter Haar syndrome (FTHS) is a rare hereditary condition associated with skeletal, cardiovascular, ocular, and craniofacial abnormalities [ 1 , 2 ]. In 1973, Frank et al (1973) initially described an 18-month-old girl born to consanguineous parents who presented with skeletal dysplasia, ocular defect, dysmorphic facial features, as well as a global developmental delay (GDD).…”

Section: Introductionmentioning

confidence: 99%

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The Role of the Disrupted Podosome Adaptor Protein (SH3PXD2B) in Frank–Ter Haar Syndrome

Massadeh

Alhabshan

AlSudairi

et al. 2022

Genes

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Frank–Ter Haar syndrome (FTHS), sometimes referred to as Ter Haar syndrome, is a rare hereditary disorder that manifests in skeletal, cardiac, and ocular anomalies, including hypertelorism, glaucoma, prominent eyes, and facial abnormalities. In this study, we performed whole-exome sequencing (WES) to identify the genetic component responsible for the phenotype of the index patient, a male infant born to a consanguineous family from Saudi Arabia. The analysis revealed a homozygous missense variant, c.280C>G, in the SH3PXD2B gene, which cosegregates with the familial phenotype with a plausible autosomal-recessive mode of inheritance, indicating a potential disease-causing association. The SH3PXD2B gene encodes a TKS4 podosome adaptor protein that regulates the epidermal growth factor signaling pathway. This study validates the critical function of the TKS4 podosome protein by suggesting a common mechanism underlying the pathogenesis of FTHS.

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“…Although several aspects of the physiological roles of Tks4 have already been revealed, the functional role of Tks4 in human embryonic development and the mechanism by which loss of Tks4 influences the complex symptoms associated with Frank-Ter Haar syndrome (FTHS, OMIM:249420) remain unknown. FTHS is a severe developmental birth defect characterized by a complex collection of phenotypes, including bone deformities (craniofacial malformations with wide fontanel and abnormal toothing, kyphosis, shortened bended bones), heart developmental defects, early onset glaucoma, reduced adipose tissue, and infertility [ 7 , 8 , 9 , 10 , 11 ]. Remarkably, FTHS severely affects skeletal bone and adipose tissue composition, all of which originate from MSCs, suggesting that MSC differentiation is disturbed during development in affected individuals.…”

Section: Introductionmentioning

confidence: 99%

A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System

László

Maczelka

Takács

et al. 2022

IJMS

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Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene (SH3PXD2b) cause a rare developmental disorder called Frank-Ter Haar syndrome (FTHS), which leads to heart abnormalities, bone tissue defects, and reduced adiposity. We aimed to produce a human stem cell-based in vitro FTHS model system to study the effects of the loss of the Tks4 protein in different cell lineages and the accompanying effects on the cell signalome. To this end, we used CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated (Cas9)) to knock out the SH3PXD2b gene in the HUES9 human embryonic stem cell line (hESC), and we obtained stable homo- and heterozygous knock out clones for use in studying the potential regulatory roles of Tks4 protein in embryonic stem cell biology. Based on pluripotency marker measurements and spontaneous differentiation capacity assays, we concluded that the newly generated Tks4-KO HUES9 cells retained their embryonic stem cell characteristics. We propose that the Tks4-KO HUES9 cells could serve as a tool for further cell differentiation studies to investigate the involvement of Tks4 in the complex disorder FTHS. Moreover, we successfully differentiated all of the clones into mesenchymal stem cells (MSCs). The derived MSC cultures showed mesenchymal morphology and expressed MSC markers, although the expression levels of mesodermal and osteogenic marker genes were reduced, and several EMT (epithelial mesenchymal transition)-related features were altered in the Tks4-KO MSCs. Our results suggest that the loss of Tks4 leads to FTHS by altering cell lineage differentiation and cell maturation processes, rather than by regulating embryonic stem cell potential.

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A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum

Cited by 14 publications

References 23 publications

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

The Role of the Disrupted Podosome Adaptor Protein (SH3PXD2B) in Frank–Ter Haar Syndrome

A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System

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