Whole exome sequencing identifies three novel mutations in <i>ANTXR1</i> in families with GAPO syndrome

Bayram, Yavuz; Pehlivan, Davut; Karaca, Ender; Gambin, Tomasz; Jhangiani, Shalini N.; Erdin, Serkan; Gonzaga‐Jauregui, Claudia; Wiszniewski, Wojciech; Elçioğlu, Nursel; Yıldırım, Mahmut Selman; Bozkurt, Banu; Zamani, Ayse Gul; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.

doi:10.1002/ajmg.a.36678

Cited by 25 publications

(19 citation statements)

References 33 publications

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“…Of these four variants, ANTXR1 was considered the strongest candidate for pathogenicity based on amino acid conservation, predictions of deleteriousness, and minor allele frequencies in the ExAC databases (in which only the ANTXR1 variant was not observed in homozygosity). Prior reports of ANTXR1 in association with pseudoanodontia provided additional evidence supporting the potential involvement of ANTXR1 in tooth development [Bayram et al 2014; Stranecky et al 2013]. Segregation analysis was performed on the ANTXR1 and KDM2B variants, and only the variant in ANTXR1 followed the expected mode of inheritance (Fig.…”

Section: Resultsmentioning

confidence: 80%

“…To date, nine different biallelic ANTXR1 variants have been suggested as etiologic for GAPO syndrome [Bayram et al 2014; Benetti-Pinto et al 2016; Chattopadhyay et al 2017; Salas-Alanis et al 2016; Stranecky et al 2013] (Fig. 2c).…”

Section: Discussionmentioning

confidence: 99%

“…Biallelic variants in ANTXR1 (anthrax toxin receptor 1) have been reported recently to be associated with GAPO syndrome (MIM#230740), which is characterized by growth retardation, alopecia, pseudoanodontia, and optic atrophy segregating as an AR trait [Bayram et al 2014; Stranecky et al 2013]. In this study, we report a novel homozygous missense variant in ANTXR1 identified by whole exome sequencing (WES) in a Turkish family with tooth agenesis.…”

Section: Introductionmentioning

confidence: 92%

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A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis

Dinçkan¹,

Du²,

Akdemir³

et al. 2018

American J of Med Genetics Pt A

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Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

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Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

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A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis

Dinçkan¹,

Du²,

Akdemir³

et al. 2018

American J of Med Genetics Pt A

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“…Homozygous ANTXR1 loss-of-function mutations cause growth retardation, alopecia, pseudo-anodontia and optic atrophy in GAPO patients [2, 14]. Additional GAPO features include prominent scalp veins, hemangioma-like vascular anomalies, and progressive skin fibrosis [3, 15].…”

Section: Introductionmentioning

confidence: 99%

Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts

Olsen

Besschetnova

2017

Matrix Biology

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Our previous studies of Antxr1 knockout mice suggested that fibrotic skin abnormalities in these mice are associated with increased VEGF signaling. Here, based on studies of primary fibroblasts isolated from skin of Antx1+/+ and Antxr1−/− mice at embryonic stage E17.5 and postnatal day P49, we conclude that increased Col1a1 and Fn1 expression in Antxr1-deficient fibroblasts is partly mediated by a cell-autonomous ANTXR1-dependent mechanism. In turn, this may act in parallel with VEGF-dependent regulation of collagen type I and fibronectin production. We demonstrate that shRNA mediated knockdown of VEGF in Antxr1 −/− fibroblasts reduces Col1a1 and Fn1 expression to below control levels, and these are restored by exogenous addition of recombinant VEGF. In addition, the increase in protein levels of collagen type I and fibronectin in mutant cells is blocked by VEGF neutralizing antibody. However, expressing the longest isoform of ANTXR1 (sv1) in mutant fibroblasts decreases levels of Ctgf, Col1a1 and Fn1 transcripts, but has no effect on VEGF expression. Taken together, our data suggest that the increased matrix production in Antxr1- deficient fibroblasts primarily occurs via a CTGF-dependent pathway and that other ANTXR1–associated mechanisms contribute to VEGF-dependent increase of collagen type I and fibronectin expression. Our findings provide a basis for further studies of novel ANTXR1-dependent connective tissue homeostatic control mechanisms in healthy individuals, patients with organ fibrosis, and patients with GAPO syndrome.

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“…They also analyzed the loss of function of these variants using fibroblasts isolated from the patients. Later, Bayram et al [2014] analyzed 5 GAPO patients from 3 unrelated Turkish families by exome sequencing, describing the presence of an indel mutation that produces a truncated protein, a missense mutation predicted to be a deleterious version of the protein, and a synonymous mutation that seems to modify a splicing site in ANTXR1 . In our study, we identified a new missense mutation (c.410A>T, Q137L) in the ANTXR1 gene in a Mexican family.…”

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confidence: 99%

New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report

et al. 2016

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GAPO syndrome is a very rare genetic disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy (GAPO). To date, only 30 cases have been described worldwide. Recently, gene alterations in the <i>ANTXR1</i> gene have been reported to be causative of this disorder, and an autosomal recessive pattern has been observed. This gene encodes a matrix-interacting protein that works as an adhesion molecule. In this report, we describe 2 homozygous siblings diagnosed with GAPO syndrome carrying a new missense mutation. This mutation produces the substitution of a glutamine in position 137 for a leucine (c.410A>T, p.Q137L).

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Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome

Cited by 25 publications

References 33 publications

A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis

A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis

Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts

New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report

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