Heterozygous variants in the teashirt zinc finger homeobox 3 (TSHZ3) gene in human congenital anomalies of the kidney and urinary tract
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články
Grantová podpora
KO5614/2-1
Deutsche Forschungsgemeinschaft (German Research Foundation)
MA9606/1-1
Deutsche Forschungsgemeinschaft (German Research Foundation)
2018_Kolleg.12, Clinician Scientist Program TITUS
Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)
PubMed
39420202
PubMed Central
PMC11711546
DOI
10.1038/s41431-024-01710-y
PII: 10.1038/s41431-024-01710-y
Knihovny.cz E-zdroje
- MeSH
- dítě MeSH
- heterozygot * MeSH
- homeodoménové proteiny genetika MeSH
- kojenec MeSH
- ledviny abnormality metabolismus MeSH
- lidé MeSH
- missense mutace MeSH
- močové ústrojí abnormality metabolismus MeSH
- multicystické dysplastické ledviny genetika MeSH
- myši MeSH
- předškolní dítě MeSH
- transkripční faktory genetika MeSH
- urogenitální abnormality genetika patologie MeSH
- vezikoureterální reflux MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- homeodoménové proteiny MeSH
- transkripční faktory MeSH
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.
Aix Marseille Univ CNRS IBDM UMR7288 Marseille France
Department of Human Genetics Hannover Medical School Hannover Germany
Department of Pediatrics 2nd Faculty of Medicine Charles University Prague Czech Republic
Department of Pediatrics Faculty of Medicine University of Ostrava Ostrava Czech Republic
Genome Analytics Research Group Helmholtz Centre for Infection Research Braunschweig Germany
Institute of Molecular Biology Hannover Medical School Hannover Germany
Nephropathology Department of Pathology Hannover Medical School Hannover Germany
Pediatric Nephrology University Children's Hospital Skopje Macedonia
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Pohl M, Bhatnagar V, Mendoza SA, Nigam SK. Toward an etiological classification of developmental disorders of the kidney and upper urinary tract. Kidney Int. 2002;61:10–19. 10.1046/j.1523-1755.2002.00086.x. PubMed
Queisser-Luft A, Stolz G, Wiesel A, Schlaefer K, Spranger J. Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990-1998). Arch Gynecol Obstet. 2002;266:163–7. 10.1007/s00404-001-0265-4. PubMed
Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiology of chronic kidney disease in children. Pediatr Nephrol. 2012;27:363–73. 10.1007/s00467-011-1939-1. PubMed PMC
Stoll C, Dott B, Alembik Y, Roth MP. Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT). Eur J Med Genet. 2014;57:322–8. 10.1016/j.ejmg.2014.04.014. PubMed
Kuure S, Sariola H. Mouse models of congenital kidney anomalies. In: Liu A, editor. Animal models of human birth defects. Singapore: Springer; 2020. pp. 109–36. PubMed
Yosypiv IV. Renin-angiotensin system in mammalian kidney development. Pediatr Nephrol. 2021;36:479–89. 10.1007/s00467-020-04496-5. PubMed
van der Ven AT, Vivante A, Hildebrandt F. Novel insights into the pathogenesis of monogenic congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2018;29:36–50. 10.1681/ASN.2017050561. PubMed PMC
Kosfeld A, Martens H, Hennies I, Haffner D, Weber RG. Kongenitale Anomalien der Nieren und ableitenden Harnwege (CAKUT). Med Genet. 2018;30:448–60. 10.1007/s11825-018-0226-y.
Sanna-Cherchi S, Westland R, Ghiggeri GM, Gharavi AG. Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest. 2018;128:4–15. 10.1172/JCI95300. PubMed PMC
Kagan M, Pleniceanu O, Vivante A. The genetic basis of congenital anomalies of the kidney and urinary tract. Pediatr Nephrol. 2022;37:2231–43. 10.1007/s00467-021-05420-1. PubMed
Kolvenbach CM, Shril S, Hildebrandt F. The genetics and pathogenesis of CAKUT. Nat Rev Nephrol. 2023;19:709–20. 10.1038/s41581-023-00742-9. PubMed
Werfel L, Martens H, Hennies I, Gjerstad AC, Fröde K, Altarescu G, et al. Diagnostic yield and benefits of whole-exome sequencing in CAKUT patients diagnosed in the first thousand days of life. Kidney Int Rep. 2023;8:2439–57. 10.1016/j.ekir.2023.08.008. PubMed PMC
Sanna-Cherchi S, Sampogna RV, Papeta N, Burgess KE, Nees SN, Perry BJ, et al. Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med. 2013;369:621–9. 10.1056/NEJMoa1214479. PubMed PMC
Vivante A, Kleppa MJ, Schulz J, Kohl S, Sharma A, Chen J, et al. Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development. Am J Hum Genet. 2015;97:291–301. 10.1016/j.ajhg.2015.07.001. PubMed PMC
Brophy PD, Rasmussen M, Parida M, Bonde G, Darbro BW, Hong X, et al. A gene implicated in activation of retinoic acid receptor targets is a novel renal agenesis gene in humans. Genetics. 2017;207:215–28. 10.1534/genetics.117.1125. PubMed PMC
Heidet L, Moriniere V, Henry C, De Tomasi L, Reilly ML, Humbert C, et al. Targeted exome sequencing identifies PBX1 as involved in monogenic congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2017;28:2901–14. 10.1681/ASN.2017010043. PubMed PMC
Münch J, Engesser M, Schonauer R, Hamm JA, Hartig C, Hantmann E, et al. Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract. Kidney Int. 2022;101:1039–53. 10.1016/j.kint.2022.01.028. PubMed PMC
Kosfeld A, Kreuzer M, Daniel C, Brand F, Schafer AK, Chadt A, et al. Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT). Hum Genet. 2016;135:69–87. 10.1007/s00439-015-1610-1. PubMed
Kosfeld A, Brand F, Weiss AC, Kreuzer M, Goerk M, Martens H, et al. Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations. Hum Mol Genet. 2017;26:1716–31. 10.1093/hmg/ddx086. PubMed
Caubit X, Lye CM, Martin E, Core N, Long DA, Vola C, et al. Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4. Development. 2008;135:3301–10. 10.1242/dev.022442. PubMed
Sanchez-Martin I, Magalhaes P, Ranjzad P, Fatmi A, Richard F, Manh TPV, et al. Haploinsufficiency of the mouse Tshz3 gene leads to kidney defects. Hum Mol Genet. 2022;31:1921–45. 10.1093/hmg/ddab362. PubMed
Nicolaou N, Pulit SL, Nijman IJ, Monroe GR, Feitz WF, Schreuder MF, et al. Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT. Kidney Int. 2016;89:476–86. 10.1038/ki.2015.319. PubMed
Feichtinger RG, Preisel M, Steinbrücker K, Brugger K, Radda A, Wortmann SB, et al. A TSHZ3 frame-shift variant causes neurodevelopmental and renal disorder consistent with previously described proximal chromosome 19q13.11 deletion syndrome. Genes. 2022;13:2191 10.3390/genes13122191. PubMed PMC
Martin E, Caubit X, Airik R, Vola C, Fatmi A, Kispert A, et al. TSHZ3 and SOX9 regulate the timing of smooth muscle cell differentiation in the ureter by reducing myocardin activity. PLoS ONE. 2013;8:e63721 10.1371/journal.pone.0063721. PubMed PMC
Bohnenpoll T, Kispert A. Ureter growth and differentiation. Semin Cell Dev Biol. 2014;36:21–30. 10.1016/j.semcdb.2014.07.014. PubMed
Bohnenpoll T, Wittern AB, Mamo TM, Weiss AC, Rudat C, Kleppa MJ, et al. A SHH-FOXF1-BMP4 signaling axis regulating growth and differentiation of epithelial and mesenchymal tissues in ureter development. PLoS Genet. 2017;13:e1006951 10.1371/journal.pgen.1006951. PubMed PMC
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43. 10.1038/s41586-020-2308-7. PubMed PMC
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. 10.1038/gim.2015.30. PubMed PMC
Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994;22:4673–80. 10.1093/nar/22.22.4673. PubMed PMC
Ciccarelli FD, Doerks T, Von Mering C, Creevey CJ, Snel B, Bork P. Toward automatic reconstruction of a highly resolved tree of life. Science. 2006;311:1283–7. 10.1126/science.1123061. PubMed
Kulharya AS, Michaelis RC, Norris KS, Taylor HA, Garcia-Heras J. Constitutional del(19)(q12q13.1) in a three-year-old girl with severe phenotypic abnormalities affecting multiple organ systems. Am J Med Genet. 1998;77:391–4. PubMed
Malan V, Raoul O, Firth HV, Royer G, Turleau C, Bernheim A, et al. 19q13.11 deletion syndrome: a novel clinically recognisable genetic condition identified by array comparative genomic hybridisation. J Med Genet. 2009;46:635–40. 10.1136/jmg.2008.062034. PubMed
Adalat S, Bockenhauer D, Ledermann SE, Hennekam RC, Woolf AS. Renal malformations associated with mutations of developmental genes: messages from the clinic. Pediatr Nephrol. 2010;25:2247–55. 10.1007/s00467-010-1578-y. PubMed PMC
Chowdhury S, Bandholz AM, Parkash S, Dyack S, Rideout AL, Leppig KA, et al. Phenotypic and molecular characterization of 19q12q13.1 deletions: a report of five patients. Am J Med Genet A. 2014;164a:62–69. 10.1002/ajmg.a.36201. PubMed
Caubit X, Gubellini P, Andrieux J, Roubertoux PL, Metwaly M, Jacq B, et al. TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nat Genet. 2016;48:1359 10.1038/ng.3681. PubMed PMC
Fasano L, Röder L, Coré N, Alexandre E, Vola C, Jacq B, et al. The gene teashirt is required for the development of Drosophila embryonic trunk segments and encodes a protein with widely spaced zinc finger motifs. Cell. 1991;64:63–79. 10.1016/0092-8674(91)90209-H. PubMed
Lye CM, Fasano L, Woolf AS. Ureter myogenesis: putting teashirt into context. J Am Soc Nephrol. 2010;21:24–30. 10.1681/ASN.2008111206. PubMed
Caubit X, Thoby-Brisson M, Voituron N, Filippi P, Bévengut M, Faralli H, et al. Teashirt 3 regulates development of neurons involved in both respiratory rhythm and airflow control. J Neurosci. 2010;30:9465–76. 10.1523/JNEUROSCI.1765-10.2010. PubMed PMC
Matsell DG, Mok A, Tarantal AF. Altered primate glomerular development due to in utero urinary tract obstruction. Kidney Int. 2002;61:1263–9. 10.1046/j.1523-1755.2002.00274.x. PubMed
Caubit X, Gubellini P, Roubertoux PL, Carlier M, Molitor J, Chabbert D, et al. Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors. Transl Psychiatry. 2022;12:106 10.1038/s41398-022-01865-6. PubMed PMC
Chabbert D, Caubit X, Roubertoux PL, Carlier M, Habermann B, Jacq B, et al. Postnatal Tshz3 deletion drives altered corticostriatal function and autism spectrum disorder–like behavior. Biol Psychiatry. 2019;86:274–85. 10.1016/j.biopsych.2019.03.974. PubMed
Christians A, Kesdiren E, Hennies I, Hofmann A, Trowe MO, Brand F, et al. Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2. Hum Genet. 2023;142:73–88. 10.1007/s00439-022-02481-6. PubMed PMC
Suriben R, Kivimae S, Fisher DA, Moon RT, Cheyette BN. Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak. Nat Genet. 2009;41:977–85. 10.1038/ng.435. PubMed PMC
Wen J, Chiang YJ, Gao C, Xue H, Xu J, Ning Y, et al. Loss of Dact1 disrupts planar cell polarity signaling by altering dishevelled activity and leads to posterior malformation in mice. J Biol Chem. 2010;285:11023–30. 10.1074/jbc.M109.085381. PubMed PMC
Hochane M, van den Berg PR, Fan X, Bérenger-Currias N, Adegeest E, Bialecka M, et al. Single-cell transcriptomics reveals gene expression dynamics of human fetal kidney development. PLoS Biol. 2019;17:e3000152. 10.1371%2Fjournal.pbio.3000152 PubMed PMC
Wang D-Z, Chang PS, Wang Z, Sutherland L, Richardson JA, Small E, et al. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell. 2001;105:851–62. 10.1016/S0092-8674(01)00404-4. PubMed
Wang D-Z, Olson EN. Control of smooth muscle development by the myocardin family of transcriptional coactivators. Curr Opin Genet Dev. 2004;14:558–66. 10.1016/j.gde.2004.08.003. PubMed
Airik R, Trowe MO, Foik A, Farin HF, Petry M, Schuster-Gossler K, et al. Hydroureternephrosis due to loss of Sox9-regulated smooth muscle cell differentiation of the ureteric mesenchyme. Hum Mol Genet. 2010;19:4918–29. 10.1093/hmg/ddq426. PubMed
Houweling AC, Beaman GM, Postma AV, Gainous TB, Lichtenbelt KD, Brancati F, et al. Loss-of-function variants in myocardin cause congenital megabladder in humans and mice. J Clin Invest. 2019;129:5374–80. 10.1172/jci128545. PubMed PMC