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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 (<jats:italic>TSHZ3<\/jats:italic>) gene. Therefore, the role of <jats:italic>TSHZ3<\/jats:italic> in human CAKUT was assessed. Twelve CAKUT patients from 9\/301 (3%) families carried five different rare heterozygous <jats:italic>TSHZ3<\/jats:italic> missense variants predicted to be deleterious. CAKUT patients with versus without <jats:italic>TSHZ3<\/jats:italic> 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 <jats:italic>Tshz3<\/jats:italic>-mutant mice and patients with heterozygous 19q12-q13.11 deletions encompassing the <jats:italic>TSHZ3<\/jats:italic> locus. Comparable with <jats:italic>Tshz3<\/jats:italic>-mutant mice, the smooth muscle layer was disorganized in the renal pelvis and thinner in the proximal ureter of the nephrectomy specimen of a <jats:italic>TSHZ3<\/jats:italic> variant carrier compared to controls. <jats:italic>TSHZ3<\/jats:italic> 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. <jats:italic>TSHZ3<\/jats:italic> variants in a 5\u2032 region were more frequent in CAKUT patients than in gnomAD samples (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). 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 <jats:italic>TSHZ3<\/jats:italic> variants are associated with human CAKUT, particularly MCDK, hydronephrosis, and hydroureter, and, inconsistently, with specific extrarenal features, including genital anomalies.<\/jats:p>","DOI":"10.1038\/s41431-024-01710-y","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T15:03:46Z","timestamp":1729177426000},"page":"44-55","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Heterozygous variants in the teashirt zinc finger homeobox 3 (TSHZ3) gene in human congenital anomalies of the kidney and urinary tract"],"prefix":"10.1038","volume":"33","author":[{"given":"Esra","family":"Kesdiren","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-3476","authenticated-orcid":false,"given":"Helge","family":"Martens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5537-8543","authenticated-orcid":false,"given":"Frank","family":"Brand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Werfel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukas","family":"Wedekind","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark-Oliver","family":"Trowe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imke","family":"Hennies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4409-016X","authenticated-orcid":false,"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoran","family":"Gucev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Seeman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-1245","authenticated-orcid":false,"given":"Velibor","family":"Tasic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2307-8428","authenticated-orcid":false,"given":"Laurent","family":"Fasano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan H.","family":"Br\u00e4sen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8154-0257","authenticated-orcid":false,"given":"Andreas","family":"Kispert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Christians","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9601-7813","authenticated-orcid":false,"given":"Dieter","family":"Haffner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6610-1080","authenticated-orcid":false,"given":"Ruthild G.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"1710_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1046\/j.1523-1755.2002.00086.x","volume":"61","author":"M Pohl","year":"2002","unstructured":"Pohl M, Bhatnagar V, Mendoza SA, Nigam SK. 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