J Am Soc Nephrol. 2015 Apr;26(4):797-804. doi: 10.1681/ASN.2013090961. Epub 2014 Aug 21.
Urinary tract effects of HPSE2 mutations.
Stuart HM1,
Roberts NA1,
Hilton EN1,
McKenzie EA2,
Daly SB1,
Hadfield KD1,
Rahal JS1,
Gardiner NJ2,
Tanley SW3,
Lewis MA1,
Sites E4,
Angle B4,
Alves C5,
Lourenço T6,
Rodrigues M6,
Calado A7,
Amado M7,
Guerreiro N7,
Serras I7,
Beetz C8,
Varga RE8,
Silay MS9,
Darlow JM10,
Dobson MG10,
Barton DE11,
Hunziker M12,
Puri P13,
Feather SA14,
Goodship JA15,
Goodship TH15,
Lambert HJ15,
Cordell HJ15;
UK VUR Study Group,
Saggar A16,
Kinali M17;
4C Study Group,
Lorenz C18,
Moeller K19,
Schaefer F20,
Bayazit AK21,
Weber S22,
Newman WG1,
Woolf AS23.
Beattie J, Bradbuty M, Coad N, Coulthard M, Cuckow P, Dossetor J, Dudley J, Hughes D, Feather S, Fitzpatrick M, Goodship JA, Goodship TH, Griffin N, Gullett AM, Haycock G, Hodes D, Houtman P, Hughes A, Hulton S, Hunter E, Iqbal J, Inward C, Jackson J, Jadresic L, Jaswon M, Jones C, Jones R, Judd B, Kier M, Kilby A, Lambert H, Lewis M, Malcolm S, Marks S, Maxwell H, McGraw M, Milford D, Moghal N, O'Connor M, O'Donoghue DJ, Ognanovic M, Plant N, Postlethwaite R, Rees L, Reid C, Rfidah E, Rigdon S, Sandford R, Savage M, Scanlan J, Sinha S, Stephens S, Stewart A, Storr J, Taheri S, Taylor CM, Tizard J, Trompeter R, Tullus K, Verber I, Van't Hoff W, Vernon S, Verrier-Jones K, Watson A, Webb N, Wilcox D, Woolf AS, Aksu N, Alpay H, Anarat A, Arbeiter K, Ardissino GL, Balat A, Baskin E, Bayazit A, Büscher R, Cakar N, Caldas Afonso A, Caliskan S, Candan C, Canpolat N, Donmez O, Doyon A, Drozdz D, Dusek J, Duzova A, Emre S, Erdogan H, Feldkötter M, Fischbach M, Galiano G, Haffner D, Harambat J, Jankauskiene A, Jeck N, John U, Jungraithmair T, Kemper M, Kiyak A, Kracht D, Kranz B, Laube G, Litwin M, Matteucci CM, Montini G, Melk A, Mir S, Niemirska A, Peco-Antic A, Ozcelik G, Pelan E, Picca S, Pohl M, Querfeld U, Ranchin B, Schaefer F, Shroff R, Simonetti G, Sözeri B, Soylemezoglu O, Tabel Y, Testa S, Trivelli A, Vidal E, Wigger M, Wühl E, Wygoda S, Yalcinkaya F, Yilmaz E, Zeller R, Zurowska AM.
- 1
- 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;
- 2
- Faculty of Life Sciences and.
- 3
- Faculty of Engineering and Physical Sciences, University of Manchester, Manchester, United Kingdom;
- 4
- Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois;
- 5
- Genetica Med. e Diagnostico Pre-Natal, Prof. Sergio Castedo, S.A., Porto, Portugal;
- 6
- Department of Medical Genetics, Hospital de Dona Estefânia, Lisboa, Portugal;
- 7
- Department of Pediatrics, Centro Hospitalar do Barlavento Algarvio, Portimão, Portugal;
- 8
- Faculty of Life Sciences and Faculty of Life Sciences and.
- 9
- Department of Urology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey;
- 10
- National Centre for Medical Genetics and National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland;
- 11
- National Centre for Medical Genetics and School of Medicine and Medical Sciences and.
- 12
- National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland;
- 13
- 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;
- 14
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom;
- 15
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
- 16
- Department of Clinical Genetics, St George's, University of London, London, United Kingdom;
- 17
- Department of Paediatric Neurology, Chelsea and Westminster Hospital and Imperial College London, and Bupa Cromwell Hospital, London, United Kingdom;
- 18
- Department of Pediatric Surgery and Urology, Klinikum Bremen-Mitte, Bremen, Germany;
- 19
- Department of Pediatrics, Klinikum Links der Weser, Bremen, Germany;
- 20
- Division of Paediatric Nephrology, Centre for Paediatric and Adolescent Medicine, University Hospital of Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany;
- 21
- Pediatric Nephrology, Cukurova University School of Medicine, Adana, Turkey; and.
- 22
- Pediatrics II, University Children's Hospital Essen, Essen, Germany.
- 23
- 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.
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.
Copyright © 2015 by the American Society of Nephrology.
KEYWORDS:
genetics and development; human genetics; molecular genetics; pediatric nephrology
Figure 1.
HPSE2 mutations in UFS and the variant in primary VUR. (A) Schematic of heparanase 2 showing location of mutations. Dark blue indicates mutations described in this report. Light blue indicates mutations from previous reports. Blue stars, nonsense or frameshift mutations; circle, missense mutation; diamond, splice-site mutation; red stars, predicted N-glycosylation sites; #, founder mutation in Ochoa’s Columbian cohort. Domains were predicted by Pfam and SignalP. N and C, the proteins amino and carboxy terminals, respectively. (B and C) Wild-type full length wild-type heparanase 2 protein (B) and the c.422_423insGCCCGG-p.Asp141delinsGluProGly variant (C). The heparanase 2 sequence was aligned to 51 α-L-arabinofuranosidase with ClustalW, and the structural model was generated using PHYRE2 (http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index).
J Am Soc Nephrol. 2015 Apr;26(4):797-804.
Figure 2.
Immunohistochemistry in wild-type mice detects UFS proteins. Sections were counterstained (blue) with hematoxylin. Positive immunodetection signals are brown. (A) Embryonic day 14. Note the similar patterns for heparanase 2 and LRIG2 in a bladder wall nerve, a nascent pelvic ganglion, a nascent lumber ganglion, mesenchymal-like cells in the wall of the proximal (i.e., top of the) ureter, and the lingual nerve. Heparanase 1 was also detected in the ganglia cell bodies but not in the nerve trunks themselves. (B–D) Serial sections of 1-week postnatal bladder immunostained for heparanase 2 (B) or LRIG2 (C). (D) The primary antibody was omitted. Note signals for both proteins in the nerve (running from top right to bottom left). (E–I) Immunohistochemistry of pelvic ganglia flanking the bladder outflow tract 2 weeks after birth: β3-tubulin, a neuronal marker (E); heparanase 2 (F); heparanase 1 (G); LRIG2 (H); negative control with no primary antibody (I). Scale bars are 50 μm.
J Am Soc Nephrol. 2015 Apr;26(4):797-804.
Figure 3.
Hpse2 mutant mouse bladder and kidney phenotypes. (A) RT-PCR of RNA from postnatal bladders. Note the abnormal Hpse2 transcript (N, 158 base pairs) in gene trap homozygous (Hom) and heterozygous (Het) tissues. The wild-type Hpse2 transcript (W, 364 base pairs) was the only one present in wild-type (Wt) mice but was not detected in homozygous (Hom) tissue. The right side of the gel shows the experiment when RT was not used. (B) Examples of “full” and “empty” bladder phenotypes in autopsies of mice in the first and second postnatal fortnights. (C) Frequencies of “full” bladder phenotypes in the three genotypes, in the first and second postnatal fortnights (total numbers analyzed are also shown). (D–O) Histology of mutant mouse bladders and kidneys; D–I are wild-type organs and J–O are homozygous mutant organs. All sections were stained with hematoxylin; I and O were also stained with eosin. Wild-type (D) and homozygous Hpse2 mutant (J) bladders at 2 weeks. Note muscle in walls of both organs. When bladders are harvested, urine can escape and organs tend to deflate. Nevertheless, an impression of the difference between homozygous and wild-type bladders is shown in the low power insets (upper right of each frame). Wild-type kidneys at 2 weeks showing sagittal section overview (E) and higher powers of papilla (F), medullary tubules (G), and glomeruli (H). Counterpart zones in littermate homozygous kidney (K–N) are grossly similar to those in wild-type organ. An area of glomerular crowding in a mutant kidney is shown in N (from area marked by asterisk in K). High-power views of outer cortex in 3-week-old kidneys from wild-type (I) and mutant (O) littermate mice. Note the small area (demarcated by arrowheads in O) of glomerular crowding and tubulo-interstitial changes next to a concavity (asterisk) in the organ’s surface. Scale bars are 50 µm.
J Am Soc Nephrol. 2015 Apr;26(4):797-804.
Publication type
MeSH terms
Substances
Supplementary concept
Grant support
Full Text Sources
Molecular Biology Databases
Research Materials