{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T13:09:23Z","timestamp":1772284163897,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,29]],"date-time":"2024-06-29T00:00:00Z","timestamp":1719619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hydronephrosis, the dilation of kidneys due to abnormal urine retention, occurs spontaneously in certain inbred mouse strains. In humans, its occurrence is often attributed to acquired urinary tract obstructions in adults, whereas in children, it can be congenital. However, the genetic factors underlying hydronephrosis pathogenesis remain unclear. We investigated the cause of hydronephrosis by analyzing tetraspanin 7 (Tspan7) gene-modified mice, which had shown a high incidence of hydronephrosis-like symptoms. We found that these mice were characterized by low liver weights relative to kidney weights and elevated blood ammonia levels, suggesting liver involvement in hydronephrosis. Gene expression analysis of the liver suggested that dysfunction of ornithine transcarbamylase (OTC), encoded by the X chromosome gene Otc and involved in the urea cycle, may contribute as a congenital factor in hydronephrosis. This OTC dysfunction may be caused by genomic mutations in X chromosome genes contiguous to Otc, such as Tspan7, or via the genomic manipulations used to generate transgenic mice, including the introduction of Cre recombinase DNA cassettes and cleavage of loxP by Cre recombinase. Therefore, caution should be exercised in interpreting the hydronephrosis phenotype observed in transgenic mice as solely a physiological function of the target gene.<\/jats:p>","DOI":"10.3390\/ijms25137203","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:58:42Z","timestamp":1719925122000},"page":"7203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Implications of Genetic Factors Underlying Mouse Hydronephrosis: Cautionary Considerations on Phenotypic Interpretation in Genetically Engineered Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0086-9817","authenticated-orcid":false,"given":"Shino","family":"Nemoto","sequence":"first","affiliation":[{"name":"Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuyo","family":"Uchida","sequence":"additional","affiliation":[{"name":"Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-9661","authenticated-orcid":false,"given":"Hiroshi","family":"Ohno","sequence":"additional","affiliation":[{"name":"Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan"},{"name":"Laboratory for Immune Regulation, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba 260-0856, Japan"},{"name":"Immunobiology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1177\/0300985811430696","article-title":"Pathobiology of aging mice and GEM: Background strains and experimental design","volume":"49","author":"Brayton","year":"2012","journal-title":"Vet. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pettan-Brewer, C., and Treuting, P.M. (2011). Practical pathology of aging mice. Pathobiol. Aging Age Relat. Dis., 1.","DOI":"10.3402\/pba.v1i0.7202"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1177\/0300985815612151","article-title":"Why animals die: An introduction to the pathology of aging","volume":"53","author":"Ward","year":"2016","journal-title":"Vet. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1258\/002367784780864893","article-title":"Inheritance of hydronephrosis in the inbred mouse strain DDD","volume":"18","author":"Goto","year":"1984","journal-title":"Lab. Anim."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1258\/002367783780959538","article-title":"Hydronephrosis in the inbred mouse strain DDD","volume":"17","author":"Nakajima","year":"1983","journal-title":"Lab. Anim."},{"key":"ref_6","first-page":"107","article-title":"Hereditary hydronephrosis in C57L\/MsNrs mice","volume":"42","author":"Takano","year":"1993","journal-title":"Jikken. Dobutsu"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1258\/002367773780944067","article-title":"Hydronephrosis in inbred strains of mice with particular reference to the BRVR strain","volume":"7","author":"Taylor","year":"1973","journal-title":"Lab. Anim."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/icb.1971.51","article-title":"Spontaneous hydronephrosis in the inbred mouse strain NZC","volume":"49","author":"Warner","year":"1971","journal-title":"Aust. J. Exp. Biol. Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0021-9975(88)90063-1","article-title":"Spontaneous hydronephrosis in C57BL\/KsJ mice","volume":"99","author":"Wright","year":"1988","journal-title":"J. Comp. Pathol."},{"key":"ref_10","unstructured":"(2024, January 06). Hydronephrosis. Available online: https:\/\/www.kidney.org\/atoz\/content\/hydronephrosis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.12669\/pjms.37.5.3951","article-title":"Etiology of hydronephrosis in adults and children: Ultrasonographic assessment in 233 patients","volume":"37","author":"Alshoabi","year":"2021","journal-title":"Pak. J. Med. Sci."},{"key":"ref_12","unstructured":"Thotakura, R., and Anjum, F. (2023). Hydronephrosis and hydroureter. StatPearls, StatPearls Publishing LLC."},{"key":"ref_13","unstructured":"Al-Salem, A.H. (2020). Hydronephrosis in infants and children. Atlas of Pediatric Surgery: Principles and Treatment, Springer International Publishing. ISBN 978-3-030-29211-9."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.jpurol.2014.10.002","article-title":"Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system)","volume":"10","author":"Nguyen","year":"2014","journal-title":"J. Pediatr. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.ucl.2023.04.001","article-title":"Ureteropelvic junction obstruction\/hydronephrosis","volume":"50","author":"Cai","year":"2023","journal-title":"Urol. Clin. N. Am."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e65307","DOI":"10.5812\/numonthly.65307","article-title":"Etiology of hydronephrosis in neonates","volume":"10","author":"Yousefichaijan","year":"2018","journal-title":"Nephro.-Urol. Mon."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6952","DOI":"10.1073\/pnas.0602087103","article-title":"Congenital progressive hydronephrosis (cph) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation","volume":"103","author":"McDill","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1084\/jem.20051984","article-title":"Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB\/c-Fcgr2b-\/-Pdcd1-\/- mice","volume":"202","author":"Okazaki","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1242\/dev.006155","article-title":"Wnt\/beta-catenin signaling regulates nephron induction during mouse kidney development","volume":"134","author":"Park","year":"2007","journal-title":"Development"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1242\/dev.022087","article-title":"A Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney","volume":"136","author":"Yu","year":"2009","journal-title":"Development"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1365-2613.2011.00762.x","article-title":"Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice","volume":"92","author":"Lee","year":"2011","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Maezawa, Y., Binnie, M., Li, C., Thorner, P., Hui, C.C., Alman, B., Taketo, M.M., and Quaggin, S.E. (2012). A new Cre driver mouse line, Tcf21\/Pod1-Cre, targets metanephric mesenchyme. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040547"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F1335","DOI":"10.1152\/ajprenal.00410.2014","article-title":"Kidney adysplasia and variable hydronephrosis, a new mutation affecting the odd-skipped related 1 gene in the mouse, causes variable defects in kidney development and hydronephrosis","volume":"308","author":"Davisson","year":"2015","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3226","DOI":"10.1016\/j.ajpath.2014.08.012","article-title":"Deletion of the miR-143\/145 cluster leads to hydronephrosis in mice","volume":"184","author":"Medrano","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1080\/08916934.2016.1261831","article-title":"Hydronephrosis with ureteritis developed in C57BL\/6N mice carrying the congenic region derived from MRL\/MpJ-type chromosome 11","volume":"50","author":"Ichii","year":"2017","journal-title":"Autoimmunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.devcel.2015.10.019","article-title":"E Proteins and ID proteins: Helix-loop-helix partners in development and disease","volume":"35","author":"Wang","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1002\/tera.1420350307","article-title":"TCDD-induced hyperplasia of the ureteral epithelium produces hydronephrosis in murine fetuses","volume":"35","author":"Abbott","year":"1987","journal-title":"Teratology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yoshioka, W., and Tohyama, C. (2019). Mechanisms of developmental toxicity of dioxins and related compounds. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030617"},{"key":"ref_29","first-page":"e52559","article-title":"A murine model of irreversible and reversible unilateral ureteric obstruction","volume":"20","author":"Hesketh","year":"2014","journal-title":"J. Vis. Exp."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1080\/0886022X.2019.1624263","article-title":"A modified relief of unilateral ureteral obstruction model","volume":"41","author":"Song","year":"2019","journal-title":"Ren. Fail."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e23339","DOI":"10.1096\/fj.202301565R","article-title":"Characterization of metabolic phenotypes and distinctive genes in mice with low-weight gain","volume":"38","author":"Nemoto","year":"2024","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Termini, C.M., and Gillette, J.M. (2017). Tetraspanins Function as Regulators of Cellular Signaling. Front. Cell Dev. Biol, 5.","DOI":"10.3389\/fcell.2017.00034"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Chen, L., Liu, H., Li, Y., Lin, X., Xia, S., Wanggou, S., and Li, X. (2023). Functional characterization of TSPAN7 as a novel indicator for immunotherapy in glioma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1105489"},{"key":"ref_34","unstructured":"(2024, January 06). Online Mendelian Inheritance in Man. Available online: https:\/\/www.omim.org\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/8904_2018_145","article-title":"Survival of a male infant with a familial Xp11.4 deletion causing ornithine transcarbamylase deficiency","volume":"45","author":"McPheron","year":"2019","journal-title":"JIMD Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1297\/cpe.19.25","article-title":"Contiguous Xp11.4 gene deletion leading to ornithine transcarbamylase deficiency detected by high-density single-nucleotide array","volume":"19","author":"Ono","year":"2010","journal-title":"Clin. Pediatr. Endocrinol."},{"key":"ref_37","first-page":"3","article-title":"Contiguous gene deletion of chromosome Xp in three families encompassing OTC, RPGR and TSPAN7 Genes","volume":"1","author":"Hartley","year":"2015","journal-title":"J. Rare Dis. Diagn. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.gene.2014.11.057","article-title":"Novel liver findings in ornithine transcarbamylase deficiency due to Xp11.4-p21.1 microdeletion","volume":"556","author":"Gallant","year":"2015","journal-title":"Gene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/21623945.2020.1861728","article-title":"Characterization of the adiponectin promoter + Cre recombinase insertion in the Tg(Adipoq-cre)1Evdr mouse by targeted locus amplification and droplet digital PCR","volume":"10","author":"Wong","year":"2021","journal-title":"Adipocyte"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/s41581-023-00742-9","article-title":"The genetics and pathogenesis of CAKUT","volume":"19","author":"Kolvenbach","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Capone, V.P., Morello, W., Taroni, F., and Montini, G. (2017). Genetics of Congenital Anomalies of the Kidney and Urinary Tract: The Current State of Play. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040796"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1258\/002367785780942651","article-title":"Influence of testosterone on hydronephrosis in the inbred mouse strain DDD","volume":"19","author":"Goto","year":"1985","journal-title":"Lab. Anim."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"E435","DOI":"10.1152\/ajpendo.00704.2006","article-title":"Testosterone exacerbates obstructive renal injury by stimulating TNF-alpha production and increasing proapoptotic and profibrotic signaling","volume":"294","author":"Metcalfe","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ymgme.2009.08.007","article-title":"Contiguous gene deletion syndrome in a female with ornithine transcarbamylase deficiency","volume":"99","author":"Balasubramaniam","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.ymgme.2008.04.011","article-title":"Complex management of a patient with a contiguous Xp11.4 gene deletion involving ornithine transcarbamylase: A role for detailed molecular analysis in complex presentations of classical diseases","volume":"94","author":"Deardorff","year":"2008","journal-title":"Mol. Genet. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bi, S., Dai, L., Jiang, L., Wang, L., Teng, M., Liu, G., and Teng, R.J. (2022). Chronic granulomatous disease associated with Duchenne muscular dystrophy caused by Xp21.1 contiguous gene deletion syndrome: Case report and literature review. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.970204"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1111\/trf.14172","article-title":"Stepwise partitioning of Xp21: A profiling method for XK deletions causative of the McLeod syndrome","volume":"57","author":"Gassner","year":"2017","journal-title":"Transfusion"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.neuron.2012.01.021","article-title":"The X-linked intellectual disability protein TSPAN7 regulates excitatory synapse development and AMPAR trafficking","volume":"73","author":"Bassani","year":"2012","journal-title":"Neuron"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Murru, L., Ponzoni, L., Longatti, A., Mazzoleni, S., Giansante, G., Bassani, S., Sala, M., and Passafaro, M. (2021). Lateral habenula dysfunctions in Tm4sf2(\u2212\/y) mice model for neurodevelopmental disorder. Neurobiol. Dis., 148.","DOI":"10.1016\/j.nbd.2020.105189"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1002\/ajmg.a.63008","article-title":"X-Linked intellectual disability update 2022","volume":"191","author":"Schwartz","year":"2023","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6570","DOI":"10.1038\/s41467-022-34264-y","article-title":"Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X","volume":"13","author":"Parenti","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_52","unstructured":"Ali, R., and Nagali, S. (2023). Hyperammonemia, StatPearls Publishing."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:07:52Z","timestamp":1760108872000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,29]]},"references-count":52,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25137203"],"URL":"https:\/\/doi.org\/10.3390\/ijms25137203","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,29]]}}}