Identification of a novel homozygous <i>ALX4</i> mutation in two unrelated patients with frontonasal dysplasia type‐2

Ruby, Mona O. El; Fayez, Alaaeldin; El-Dessouky, Sara H; Aglan, Mona; Mazen, Inas; Ismail, Nora; Afifi, Hanan H.; Eid, Maha M.; Mostafa, Mostafa I.; Mehrez, Mennat I.; Khalil, Yasmin; Zaki, Maha S.; Gaber, Khaled R.; Abdel‐Hamid, Mohamed S.; Abdel-Salam, Ghada M.H.

doi:10.1002/ajmg.a.38655

Cited by 8 publications

(4 citation statements)

References 14 publications

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“…These observations establish alx1 as a conserved, pivotal regulator of echinoderm skeletogenesis. Strikingly, the closest relatives of echinoderm alx1 in vertebrates (Cart1/alx1, alx3, and alx4) also control the development of skeletal structures, including facial bones and the scapula, in mice (12)(13)(14)(15)(16), humans (17)(18)(19)(20)(21) and other vertebrates (22,23).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the DNA-binding properties of Alx1, an evolutionarily conserved regulator of skeletogenesis in echinoderms

Guerrero-Santoro

Khor

Açıkbaş

et al. 2021

Journal of Biological Chemistry

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Section: Introductionmentioning

confidence: 99%

Analysis of the DNA-binding properties of Alx1, an evolutionarily conserved regulator of skeletogenesis in echinoderms

Guerrero-Santoro

Khor

Açıkbaş

et al. 2021

Journal of Biological Chemistry

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“…From previous RNA seq analysis together with our in situ hybridization analyses, we identified a significant reduction in Alx1 and Alx3 expression in the developing frontonasal process of RA signaling–deficient embryos. Alx homeobox transcription factors such as Alx1 , Alx3 , and Alx4 have been associated with distinct types of human frontonasal dysplasia that include midfacial cleft (Twigg et al 2009; Uz et al 2010; El-Ruby et al 2018). Moreover, the midfacial cleft is the result of elevated apoptosis in the frontonasal mesenchyme of Alx3/4 compound mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Deficiency Underlies the Etiology of Midfacial Defects

Kurosaka

Wang

et al. 2022

J Dent Res

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Embryonic craniofacial development depends on the coordinated outgrowth and fusion of multiple facial primordia, which are populated with cranial neural crest cells and covered by the facial ectoderm. Any disturbance in these developmental events, their progenitor tissues, or signaling pathways can result in craniofacial deformities such as orofacial clefts, which are among the most common birth defects in humans. In the present study, we show that Rdh10 loss of function leads to a substantial reduction in retinoic acid (RA) signaling in the developing frontonasal process during early embryogenesis, which results in a variety of craniofacial anomalies, including midfacial cleft and ectopic chondrogenic nodules. Elevated apoptosis and perturbed cell proliferation in postmigratory cranial neural crest cells and a substantial reduction in Alx1 and Alx3 transcription in the developing frontonasal process were associated with midfacial cleft in Rdh10-deficient mice. More important, expanded Shh signaling in the ventral forebrain, as well as partial abrogation of midfacial defects in Rdh10 mutants via inhibition of Hh signaling, indicates that misregulation of Shh signaling underlies the pathogenesis of reduced RA signaling-associated midfacial defects. Taken together, these data illustrate the precise spatiotemporal function of Rdh10 and RA signaling during early embryogenesis and their importance in orchestrating molecular and cellular events essential for normal midfacial development.

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“…38 We tested the predicted pathogenic variant, p.G369E, and found a decrease in luciferase activity, suggesting that this variant could affect the transcriptional activity of ALX4 state. 37 The mode of inheritance of ALX4 variant seems to be complex. In some cases, is it autosomal recessive, in others autosomal dominant, and in others could be polygenic.…”

Section: Ta B L E 1 (Continued)mentioning

confidence: 99%

“…24,25 The penetrance and the expressivity of the different Lst phenotypes are sensitive to genetic background, with homozygous mutant mice having a range of phenotypes that includes polydactyly of all four limbs, craniofacial defects, dorsal alopecia, weakness of the ventral body wall, open eyelids at birth, and, in males, anomalies of the phallus and cryptorchidism. [26][27][28][29] Mutations in and/or deletions of ALX4 have been associated with several developmental disorders, such as autosomal dominant parietal foramina, [30][31][32][33][34] autosomal recessive frontonasal dysplasia, [35][36][37] craniosynostosis, 38 and Potocki-Shaffer syndrome, which can include GU defects. 30,39,40 As the mouse Alx4 phenotype involves GU defects ranging from common cryptorchidism to rare epispadias, and because these defects intersect with our interest in understanding the genetic basis of GU defects, variants in ALX4 were investigated in a cohort of individuals undergoing clinical exome sequencing (ES) as well as a different cohort of 52 children who presented with BEEC.…”

Section: Introductionmentioning

confidence: 99%

Variants in ALX4 and their association with genitourinary defects

et al. 2020

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Background Genitourinary anomalies occur in approximately 1% of humans, but in most cases, the cause is unknown. Aristaless‐like homeobox 4 (ALX4) is an important homeodomain transcription factor. ALX4 mutations in humans and mouse have been associated with craniofacial defects and genitourinary anomalies such as cryptorchidism and epispadias. Objectives To investigate the presence and the functional impact of ALX4 variants in patients with genitourinary defects. Materials and methods Two separate patient cohorts were analyzed. One includes clinical exome‐sequencing (ES) data from 7500 individuals. The other includes 52 ALX4 Sanger‐sequenced individuals with bladder exstrophy‐epispadias complex (BEEC). Dual luciferase assays were conducted to investigate the functional transcriptional impact of ALX4 variants in HeLa cells and HEK293 cells. Results A total of 41 distinct ALX4 heterozygous missense variants were identified in the ES cohort with 15 variants present as recurrent in multiple patients. p.G369E and p.L373F were the only two present in individuals with genitourinary defects. A p.L373F heterozygous variant was also identified in one of the 52 individuals in the BEEC cohort. p.L373F and p.G369E were tested in vitro as both are considered damaging by MutationTaster, although only p.G369E was considered damaging by PolyPhen‐2. p.L373F did not alter transcriptional activity in HeLa and HEK293 cells. p.G369E caused a significant 3.4‐ and 1.8‐fold decrease in transcriptional activities relative to wild‐type ALX4 in HEK293 and HeLa cells, respectively. Discussion and conclusions Our study supports the idea that transcription factors like ALX4 could influence the normal development of the GU tract in humans as demonstrated in mouse models as ALX4 variant p.G369E (predicted pathogenic by multiple databases) affects ALX4 function in vitro. Variant p.L373F (predicted pathogenic by only MutationTaster) did not affect ALX4 function in vitro. Exon‐sequence information and mouse genetics provide important insights into the complex mechanisms driving genitourinary defects allowing the association of transcriptional defects with congenital disorders.

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Identification of a novel homozygous ALX4 mutation in two unrelated patients with frontonasal dysplasia type‐2

Cited by 8 publications

References 14 publications

Analysis of the DNA-binding properties of Alx1, an evolutionarily conserved regulator of skeletogenesis in echinoderms

Analysis of the DNA-binding properties of Alx1, an evolutionarily conserved regulator of skeletogenesis in echinoderms

Retinoic Acid Deficiency Underlies the Etiology of Midfacial Defects

Variants in ALX4 and their association with genitourinary defects

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