title: Urinary tract effects of HPSE2 mutations.
abstract: Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: Helen M
authors.initials: HM
authors.lastname: Stuart
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: Neil A
authors.initials: NA
authors.lastname: Roberts
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: Emma N
authors.initials: EN
authors.lastname: Hilton
authors.affiliation: Faculty of Life Sciences and.
authors.forename: Edward A
authors.initials: EA
authors.lastname: McKenzie
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Daly
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Hadfield
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Rahal
authors.affiliation: Faculty of Life Sciences and.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Gardiner
authors.affiliation: Faculty of Engineering and Physical Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Simon W
authors.initials: SW
authors.lastname: Tanley
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Lewis
authors.affiliation: Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois;
authors.forename: Emily
authors.initials: E
authors.lastname: Sites
authors.affiliation: Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois;
authors.forename: Brad
authors.initials: B
authors.lastname: Angle
authors.affiliation: Genetica Med. e Diagnostico Pre-Natal, Prof. Sergio Castedo, S.A., Porto, Portugal;
authors.forename: Cláudia
authors.initials: C
authors.lastname: Alves
authors.affiliation: Department of Medical Genetics, Hospital de Dona Estefânia, Lisboa, Portugal;
authors.forename: Teresa
authors.initials: T
authors.lastname: Lourenço
authors.affiliation: Department of Medical Genetics, Hospital de Dona Estefânia, Lisboa, Portugal;
authors.forename: Márcia
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: Department of Pediatrics, Centro Hospitalar do Barlavento Algarvio, Portimão, Portugal;
authors.forename: Angelina
authors.initials: A
authors.lastname: Calado
authors.affiliation: Department of Pediatrics, Centro Hospitalar do Barlavento Algarvio, Portimão, Portugal;
authors.forename: Marta
authors.initials: M
authors.lastname: Amado
authors.affiliation: Department of Pediatrics, Centro Hospitalar do Barlavento Algarvio, Portimão, Portugal;
authors.forename: Nancy
authors.initials: N
authors.lastname: Guerreiro
authors.affiliation: Department of Pediatrics, Centro Hospitalar do Barlavento Algarvio, Portimão, Portugal;
authors.forename: Inês
authors.initials: I
authors.lastname: Serras
authors.affiliation: Faculty of Life Sciences and Faculty of Life Sciences and.
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.affiliation: Faculty of Life Sciences and Faculty of Life Sciences and.
authors.forename: Rita-Eva
authors.initials: RE
authors.lastname: Varga
authors.affiliation: Department of Urology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey;
authors.forename: Mesrur Selcuk
authors.initials: MS
authors.lastname: Silay
authors.affiliation: National Centre for Medical Genetics and National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland;
authors.forename: John M
authors.initials: JM
authors.lastname: Darlow
authors.affiliation: National Centre for Medical Genetics and National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland;
authors.forename: Mark G
authors.initials: MG
authors.lastname: Dobson
authors.affiliation: National Centre for Medical Genetics and School of Medicine and Medical Sciences and.
authors.forename: David E
authors.initials: DE
authors.lastname: Barton
authors.affiliation: National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland;
authors.forename: Manuela
authors.initials: M
authors.lastname: Hunziker
authors.affiliation: National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland; School of Medicine and Medical Sciences and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland;
authors.forename: Prem
authors.initials: P
authors.lastname: Puri
authors.affiliation: Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom;
authors.forename: Sally A
authors.initials: SA
authors.lastname: Feather
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Lambert
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Department of Clinical Genetics, St George's, University of London, London, United Kingdom;
authors.forename: Anand
authors.initials: A
authors.lastname: Saggar
authors.affiliation: Department of Paediatric Neurology, Chelsea and Westminster Hospital and Imperial College London, and Bupa Cromwell Hospital, London, United Kingdom;
authors.forename: Maria
authors.initials: M
authors.lastname: Kinali
authors.affiliation: Department of Pediatric Surgery and Urology, Klinikum Bremen-Mitte, Bremen, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Lorenz
authors.affiliation: Department of Pediatrics, Klinikum Links der Weser, Bremen, Germany;
authors.forename: Kristina
authors.initials: K
authors.lastname: Moeller
authors.affiliation: Division of Paediatric Nephrology, Centre for Paediatric and Adolescent Medicine, University Hospital of Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany;
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.affiliation: Pediatric Nephrology, Cukurova University School of Medicine, Adana, Turkey; and.
authors.forename: Aysun K
authors.initials: AK
authors.lastname: Bayazit
authors.affiliation: Pediatrics II, University Children's Hospital Essen, Essen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom;
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, United Kingdom; adrian.woolf@manchester.ac.uk.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
mesh_terms: D000818:Animals; D019066:Facies; D005260:Female; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D014551:Urinary Tract / Q000503:physiopathology*; D014570:Urologic Diseases / Q000235:genetics* / Q000503:physiopathology; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase
keywords: genetics and development; human genetics; molecular genetics; pediatric nephrology