Variants in ALX4 and their association with genitourinary defects.

Autor: Chen CH; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA., Bournat JC; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA., Wilken N; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA.; Department of Urology, Baylor College of Medicine, Houston, TX, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX, USA., Zhang J; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA., Seth A; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA.; Department of Urology, Baylor College of Medicine, Houston, TX, USA.; Division of Urology, Department of Surgery, Texas Children's Hospital, Houston, TX, USA., Jorgez CJ; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA.; Department of Urology, Baylor College of Medicine, Houston, TX, USA.; Division of Urology, Department of Surgery, Texas Children's Hospital, Houston, TX, USA.
Jazyk: angličtina
Zdroj: Andrology [Andrology] 2020 Sep; Vol. 8 (5), pp. 1243-1255. Date of Electronic Publication: 2020 Jul 16.
DOI: 10.1111/andr.12815
Abstrakt: 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.
(© 2020 American Society of Andrology and European Academy of Andrology.)
Databáze: MEDLINE
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