Urinary Tract Effects of HPSE2 Mutations

H M Stuart, N A Roberts, E N Hilton, Edward Mckenzie, S B Daly, K D Hadfield, J S Rahal, N J Gardiner, S W Tanley, M A Lewis, E Sites, B Angle, C Alves, T Lourenco, M Rodrigues, A Calado, M Amado, N Guerreiro, I Serras, C BeetzR E Varga, M S Silay, J M Darlow, M G Dobson, D E Barton, M Hunziker, P Puri, S A Feather, J A Goodship, T H Goodship, H J Lambert, H J Cordell, UK VUR Study Group, A Saggar, M Kinali, C Lorenz, K Moeller, F Schaefer, A K Bayazit, S Weber, W G Newman, Adrian S Woolf

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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.
Original languageEnglish
Pages (from-to)797-804
Number of pages7
JournalJ Am Soc Nephrol
Volume26
Issue number4
DOIs
Publication statusPublished - Apr 2015

Keywords

  • genetics and development
  • human genetics
  • molecular genetics
  • pediatric nephrology

Research Beacons, Institutes and Platforms

  • Manchester Institute of Biotechnology

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