{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T09:57:09Z","timestamp":1792231029010,"version":"4.4.0"},"reference-count":59,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Andrology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Genitourinary anomalies occur in approximately 1% of humans, but in most cases, the cause is unknown. Aristaless\u2010like homeobox 4 (<jats:italic>ALX4<\/jats:italic>) is an important homeodomain transcription factor. <jats:italic>ALX4<\/jats:italic> mutations in humans and mouse have been associated with craniofacial defects and genitourinary anomalies such as cryptorchidism and epispadias.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To investigate the presence and the functional impact of <jats:italic>ALX4<\/jats:italic> variants in patients with genitourinary defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Two separate patient cohorts were analyzed. One includes clinical exome\u2010sequencing (ES) data from 7500 individuals. The other includes 52 <jats:italic>ALX4<\/jats:italic> Sanger\u2010sequenced individuals with bladder exstrophy\u2010epispadias complex (BEEC). Dual luciferase assays were conducted to investigate the functional transcriptional impact of <jats:italic>ALX4<\/jats:italic> variants in HeLa cells and HEK293 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 41 distinct <jats:italic>ALX4<\/jats:italic> 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\u20102. p.L373F did not alter transcriptional activity in HeLa and HEK293 cells. p.G369E caused a significant 3.4\u2010 and 1.8\u2010fold decrease in transcriptional activities relative to wild\u2010type <jats:italic>ALX4<\/jats:italic> in HEK293 and HeLa cells, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and conclusions<\/jats:title><jats:p>Our study supports the idea that transcription factors like <jats:italic>ALX4<\/jats:italic> could influence the normal development of the GU tract in humans as demonstrated in mouse models as <jats:italic>ALX4<\/jats:italic> variant p.G369E (predicted pathogenic by multiple databases) affects <jats:italic>ALX4<\/jats:italic> function in vitro. Variant p.L373F (predicted pathogenic by only MutationTaster) did not affect <jats:italic>ALX4<\/jats:italic> function in vitro. Exon\u2010sequence information and mouse genetics provide important insights into the complex mechanisms driving genitourinary defects allowing the association of transcriptional defects with congenital disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.12815","type":"journal-article","created":{"date-parts":[[2020,5,9]],"date-time":"2020-05-09T08:45:40Z","timestamp":1589013940000},"page":"1243-1255","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Variants in <i>ALX4<\/i> and their association with genitourinary defects"],"prefix":"10.1111","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-3036","authenticated-orcid":false,"given":"Ching H.","family":"Chen","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan 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