Urinary Tract Effects of HPSE2 Mutations

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

J Am Soc Nephrol. 2014 Aug 26; 26(4):797-804


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.

Read More on PubMed