A Rare Case Report of Frank Ter Haar Syndrome in a Sibling Pair Presenting With Congenital Glaucoma

Ratukondla, Banushree; Prakash, Sarvesswaran; Reddy, Sindhura; Puthuran, George Varghese; Kannan, Naresh Babu; Pillai, Manju

doi:10.1097/ijg.0000000000001420

Cited by 7 publications

(9 citation statements)

References 8 publications

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“…Other skeletal malformations, including bowing and shortened long bones and kyphosis, are often associated with FTHS, and the most fatal consequences of the disease are cardiac anomalies caused by valve or septal defects. 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].…”

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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“…FTHS is a recessive hereditary disease caused by mutations of the SH3PXD2B (SH3 and PX domains 2B) gene on chromosome 5q35; this gene codes for the TKS4 podosome adaptor protein, which regulates the epidermal growth factor signaling pathway [ 2 , 11 ]. Table 2 summarizes all SH3PXD2B variants reported to be associated with the FTHS phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…FTHS is one of the exceptions, as we have adequate scientific background information about the single causative gene mutation (i.e., in the S H3PXD2b gene) that leads to the FTHS phenotypes [ 12 ]. Since the discovery of this monogenic disease, a moderate scientific effort has been dedicated to investigating the how the functions of Tks4, which is encoded by the SH3PXD2b gene, exert their effects on FTHS-affected tissues [ 4 , 5 , 24 , 25 ]. Three different mouse models have been generated to study the effects of Tks4 loss in vivo and these studies provided information about how Tks4 regulates bone and adipose tissue homeostasis [ 12 , 26 , 27 ].…”

Section: Discussionmentioning

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 Rare Case Report of Frank Ter Haar Syndrome in a Sibling Pair Presenting With Congenital Glaucoma

Cited by 7 publications

References 8 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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