New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report

Salas‐Alanís, Julio C.; Scott, Claire A.; Fajardo-Ramírez, Óscar R; Duran, Carola; Moreno-Treviño, María Guadalupe; Kelsell, David P.

doi:10.1159/000446619

Cited by 9 publications

(8 citation statements)

References 12 publications

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“…[209][210][211][212] Autosomal recessively inherited mutations in ANTXR1, encoding anthrax toxin receptor 1, have been described as causative of GAPO syndrome with a wide spectrum of mutations. 208,209,213,214 2.4.2 | Hallermann-Streiff Syndrome (MIM %234100)…”

Section: Gapo Syndrome (Mim #230740)mentioning

confidence: 99%

Premature aging disorders: A clinical and genetic compendium

2020

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Progeroid disorders make up a heterogeneous group of very rare hereditary diseases characterized by clinical signs that often mimic physiological aging in a premature manner. Apart from Hutchinson-Gilford progeria syndrome, one of the bestinvestigated progeroid disorders, a wide spectrum of other premature aging phenotypes exist, which differ significantly in their clinical presentation and molecular pathogenesis. Next-generation sequencing (NGS)-based approaches have made it feasible to determine the molecular diagnosis in the early stages of a disease. Nevertheless, a broad clinical knowledge on these disorders and their associated symptoms is still fundamental for a comprehensive patient management and for the interpretation of variants of unknown significance from NGS data sets. This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well-known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options. K E Y W O R D S characteristic clinical features, hereditary, premature aging, progeroid disorders 1 | INTRODUCTION Aging is a general biological phenomenon that affects all human beings and results in a functional decline of physiological systems accompanied by an increased risk for chronic ailments with advancing chronological age. 1,2 At the molecular level, aging is for example associated with genomic instability, loss of heterochromatin, and the accumulation of macromolecular damage leading to reduced (stem) cell function and tissue regeneration. 3 Progeroid disorders show many clinical features of aging-associated pathologies and signs similar to physiological aging; however, they occur at earlier ages and often progress rapidly. In many aspects progeria therefore represents a timelapse form of aging. Premature aging processes are mostly segmental in that they involve one or more organs, but do not exhibit all aspects associated with physiological aging. Premature aging signs include, among others, alopecia, hair graying, lipodystrophy, osteoporosis, joint contractures, cataract, hearing loss, atherosclerosis, cardiovascular diseases, diabetes mellitus and malignancies at an early age. In addition to these typical aging phenotypes, progeria patients may also present with growth retardation, developmental delay, and intellectual disability. A more modular view of segmental premature aging syndromes hypothesizes that a cluster of symptoms appearing in several disorders might be due to a common underlying cause-for example, alopecia, osteoporosis and nail atrophy have been proposed to be related to telomere shortening. 4 Research into premature aging disorders aims at understanding the pathogenesis and to develop novel treatment strategies, but also intends to unshadow physiological aging processes since premature aging phenotypes mirror many of the clinical aspects of physiological aging. 3 One of the best-known premature aging disorders is the Hutchinson-Gilford progeria syndr...

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Section: Gapo Syndrome (Mim #230740)mentioning

confidence: 99%

Premature aging disorders: A clinical and genetic compendium

2020

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“…Gly89Arg located in the VWA domain were also identified in two families affected with GAPO syndrome, one of Hispanic and one of South Asian descent, respectively (Chattopadhyay et al, 2017;Salas-Alanis et al, 2016). In addition, a splice site mutation c.378+3A>G; p.…”

Section: Discussionmentioning

confidence: 97%

“…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%

“…The c.411A>G and c.1221dupT variants reside within VWA and Ant_C domain respectively and c.1150G>A located at a highly conserved site [Bayram et al 2014]. Two missense variants (c.410A>T [p.Gln137Leu] and c.265G>A [p.Gly89Arg]) located in the VWA domain were also identified in two families affected with GAPO syndrome, one of Hispanic and one of South Asian descent, respectively [Chattopadhyayet al 2017; Salas-Alaniset al 2016]. In addition, a splice site mutation c.378+3A>G (p.[Arg99_Arg126del]) was indicated to result in exon 4 skipping in a Brazilian GAPO syndrome patient also affected with premature ovarian insufficiency [Benetti-Pinto et al 2016].…”

Section: Discussionmentioning

confidence: 99%

“…To date, nine different biallelic ANTXR1 variants have been suggested as etiologic for GAPO syndrome (Bayram et al, 2014;Benetti-Pinto, Ferreira, Andrade, Yela, & De Mello, 2016;Chattopadhyay et al, 2017;Salas-Alanis et al, 2016;Stranecky et al, 2013) (Figure 2c | 1019 syndrome patients (Stranecky et al, 2013). The nonsense variants reside within the VWA domain, whereas the splice site variant was predicted to abolish a splicing acceptor site of the ANTXR1 transcript.…”

Section: Discussionmentioning

confidence: 99%

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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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GAPO syndrome in seven new patients: Identification of five novel ANTXR1 mutations including the first large intragenic deletion

Abdel‐Hamid

Ismail

Zaki

et al. 2018

American J of Med Genetics Pt A

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GAPO syndrome is a very rare disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy. It is caused by biallelic mutations in the ANTXR1 gene. Herein, we describe the clinical and molecular findings of seven new patients with GAPO syndrome. Our patients presented with the characteristic clinical features of the syndrome except for one patient who did not display total alopecia till the age of two years. Strikingly, optic atrophy and glaucoma were observed in all patients and one patient showed keratopathy in addition. Moreover, craniosynstosis was an unusual associated finding in one patient. Mutational analysis of ANTXR1 gene identified five novel homozygous mutations including two frameshift, two splice site and a large intragenic deletion of exon 3. Our results reinforce the clinical characteristics of the syndrome, expand the mutational spectrum and provide more insights into the role of the ANTXR1 protein in the regulation of extracellular matrix.

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New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report

Cited by 9 publications

References 12 publications

Premature aging disorders: A clinical and genetic compendium

Premature aging disorders: A clinical and genetic compendium

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

GAPO syndrome in seven new patients: Identification of five novel ANTXR1 mutations including the first large intragenic deletion

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