Heterozygous variants in the teashirt zinc finger homeobox 3 (TSHZ3) gene in human congenital anomalies of the kidney and urinary tract.

Autor: Kesdiren E; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Martens H; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Brand F; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Werfel L; Department of Human Genetics, Hannover Medical School, Hannover, Germany.; Department of Pediatric Kidney, Liver, Metabolic and Neurological Diseases, Hannover Medical School, Hannover, Germany., Wedekind L; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany., Trowe MO; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany., Schmitz J; Nephropathology, Department of Pathology, Hannover Medical School, Hannover, Germany., Hennies I; Department of Pediatric Kidney, Liver, Metabolic and Neurological Diseases, Hannover Medical School, Hannover, Germany., Geffers R; Genome Analytics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany., Gucev Z; Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia., Seeman T; Department of Pediatrics, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.; Department of Pediatrics, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic., Schmidt S; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany., Tasic V; Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia., Fasano L; Aix-Marseille Univ, CNRS, IBDM UMR7288, Marseille, France., Bräsen JH; Nephropathology, Department of Pathology, Hannover Medical School, Hannover, Germany., Kispert A; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany., Christians A; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Haffner D; Department of Pediatric Kidney, Liver, Metabolic and Neurological Diseases, Hannover Medical School, Hannover, Germany., Weber RG; Department of Human Genetics, Hannover Medical School, Hannover, Germany. weber.ruthild@mh-hannover.de.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Oct 17. Date of Electronic Publication: 2024 Oct 17.
DOI: 10.1038/s41431-024-01710-y
Abstrakt: Around 180 genes have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in mice, and represent promising novel candidate genes for human CAKUT. In whole-exome sequencing data of two siblings with genetically unresolved multicystic dysplastic kidneys (MCDK), prioritizing variants in murine CAKUT-associated genes yielded a rare variant in the teashirt zinc finger homeobox 3 (TSHZ3) gene. Therefore, the role of TSHZ3 in human CAKUT was assessed. Twelve CAKUT patients from 9/301 (3%) families carried five different rare heterozygous TSHZ3 missense variants predicted to be deleterious. CAKUT patients with versus without TSHZ3 variants were more likely to present with hydronephrosis, hydroureter, ureteropelvic junction obstruction, MCDK, and with genital anomalies, developmental delay, overlapping with the previously described phenotypes in Tshz3-mutant mice and patients with heterozygous 19q12-q13.11 deletions encompassing the TSHZ3 locus. Comparable with Tshz3-mutant mice, the smooth muscle layer was disorganized in the renal pelvis and thinner in the proximal ureter of the nephrectomy specimen of a TSHZ3 variant carrier compared to controls. TSHZ3 was expressed in the human fetal kidney, and strongly at embryonic day 11.5-14.5 in mesenchymal compartments of the murine ureter, kidney, and bladder. TSHZ3 variants in a 5' region were more frequent in CAKUT patients than in gnomAD samples (p < 0.001). Mutant TSHZ3 harboring N-terminal variants showed significantly altered SOX9 and/or myocardin binding, possibly adversely affecting smooth muscle differentiation. Our results provide evidence that heterozygous TSHZ3 variants are associated with human CAKUT, particularly MCDK, hydronephrosis, and hydroureter, and, inconsistently, with specific extrarenal features, including genital anomalies.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: