title: A mouse model of urofacial syndrome with dysfunctional urination.
abstract: Urofacial syndrome (UFS) is an autosomal recessive disease with severe dysfunctional urination including urinary incontinence (UI). Biallelic mutations of HPSE2 are discovered from UFS patients, suggesting that HPSE2 is a candidate disease gene. Here, we show that deletion of Hpse2 is sufficient to cause the UFS-like phenotype in mice. Hpse2 knockout mutants display a distended bladder (megacystis) phenotype and abnormal voiding behavior similar to that found in patients. While Hpse2 is largely dispensable for detrusor smooth muscle and urothelial cell fate determination, the mutants have significantly lower rates of cell proliferation than wild-type littermate controls. All Hpse2 mutants have a growth retardation phenotype and die within a month after birth. Comprehensive blood chemistry and urinalysis indicate that Hpse2 mutants have renal dysfunction and malnutrition. We provide evidence that transforming growth factor beta (Tgfβ) signaling is attenuated at birth. However, Tgfβ activity is significantly enhanced at later stages when the urological phenotype is severe, and the mutant bladders have accumulated excessive amount of fibrotic tissue. Together, these findings strongly suggest that Hpse2 is a causative gene of human UFS and further uncover unexpected roles of Hpse2 in bladder physiology, tissue remodeling and Tgfβ signaling.
authors.affiliation: Departments of Urology and Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA, Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Guo
authors.affiliation: Departments of Urology and Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA, Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Departments of Urology and Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA, Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Departments of Urology and Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel and.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Pediatric Surgery, The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China sean.li@childrens.harvard.edu wmclzr@163.com.
authors.forename: Zhong-Rong
authors.initials: ZR
authors.lastname: Li
authors.affiliation: Departments of Urology and Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA, Department of Surgery, Harvard Medical School, Boston, MA, USA, sean.li@childrens.harvard.edu wmclzr@163.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019066:Facies; D005260:Female; D017353:Gene Deletion; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014570:Urologic Diseases / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D016212:Transforming Growth Factor beta; D000099175:Heparanase