Alternative titles; symbols
HGNC Approved Gene Symbol: HPSE2
SNOMEDCT: 236533008;
Cytogenetic location: 10q24.2 Genomic coordinates (GRCh38) : 10:98,457,077-99,315,951 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.2 | Urofacial syndrome 1 | 236730 | Autosomal recessive | 3 |
Heparan sulfate proteoglycans (HSPGs) are major components of the basement membrane and extracellular matrix. Heparanases, like HSPE2, are endoglycosidases that cleave the heparan sulfate side chain of HSPGs to permit the remodeling of the extracellular matrix for cell movement or the release of bioactive molecules from the extracellular matrix or cell surface (summary by McKenzie et al., 2000).
By searching an EST database for sequences similar to HPA1 (HPSE; 604724), followed by PCR of a normal mammary gland cDNA library, McKenzie et al. (2000) identified 3 HPSE2 splice variants that they called HPA2A, HPA2B, and HPA2C. The 3 transcripts encode 480-, 534-, and 592-amino acid proteins, respectively. All 3 proteins have an N-terminal transmembrane domain and a C-terminal heparin-binding motif. HPA2AB and HPA2C differ from HPA2A by the insertion of 45 or 112 amino acids, respectively, after asp149. Northern blot analysis detected a 4.4-kb transcript in bladder, small intestine, uterus, and prostate. Real-time quantitative RT-PCR detected highest HPA2 expression in brain, mammary gland, prostate, small intestine, testis, and uterus, with little or no expression in most other normal tissues examined. In brain subregions, highest HPA2 expression was detected in caudate nucleus, thalamus, and cerebellum. RNA dot blot analysis also showed high HPA2 expression in aorta and brain medulla oblongata, putamen, and pons. McKenzie et al. (2000) noted that the pattern of HPA2 expression differed from that of HPA1 in both normal and tumor tissues.
In a human multiple-tissue RNA dot blot, Daly et al. (2010) observed widespread HPSE2 expression in the adult central nervous system, including the spinal cord, caudate nucleus, thalamus, substantia nigra, medulla oblongata, putamen, and pons. As assessed by RT-PCR of a human embryonic brain panel, HPSE2 was expressed in the developing forebrain, telencephalon, diencephalon, midbrain, hindbrain, and spinal cord. Dot-blot analysis also showed prominent HPSE2 expression in the adult urinary bladder, and in situ hybridization demonstrated that transcripts localized within tissue sections to longitudinal and circular layers of detrusor muscle. On dot blots, there was also evidence that HPSE2 is expressed in the adult fore-, mid-, and lower gut and in both the adult and fetal kidney.
Roberts et al. (2014) found that the 580-amino acid Xenopus Hpse2 protein shares 80% identity with human HPSE2. Both proteins are predicted to lack the endo-beta-D-glucuronidase activity found in HPSE1 (HPSE; 604724). Expression of Hpse2 increased with development in Xenopus embryos, first being detected in neural tube and myotomes, and later in skeletal muscle and gut epithelium.
By radiation hybrid analysis, McKenzie et al. (2000) mapped the HPSE2 gene to chromosome 10q23-q24.
De Moura et al. (2009) found that the expression of HPSE2 was elevated in malignant and benign epithelial ovarian neoplasias compared with normal ovarian tissue. They concluded that HPSE2 is involved in neoplastic proliferation, but not specifically malignant neoplasia.
In a patient from a Colombian family with urofacial syndrome mapping to chromosome 10q24 (UFS1; 236730), Pang et al. (2010) analyzed multiple candidate genes and identified homozygosity for a nonsense mutation in HPSE2 (613469.0001). Analysis of 5 more Colombian UFS families revealed homozygosity for the same mutation in all patients. Screening of the HPSE2 gene in 2 UFS families from the United States revealed homozygosity for a 2-bp deletion in affected individuals (613469.0002), and in a French UFS family, patients were found to be compound heterozygous for the same 2-bp deletion and another 2-bp deletion (613469.0003).
In a consanguineous British Pakistani family with UFS mapping to 10q23-q24, Daly et al. (2010) performed copy number analysis and identified homozygosity for an intragenic deletion involving exons 8 and 9 of the HPSE2 gene that segregated with the disease (613469.0004). Mutation screening of HPSE2 led to the identification of homozygosity for 2 nonsense and 3 frameshift mutations in 5 previously reported unrelated UFS families from Ireland, Spain, and Turkey (613469.0002; 613469.0005-613469.0008, respectively).
In 3 sisters, born of first-cousin Pakistani parents, with UFS, Mahmood et al. (2012) identified homozygosity for a missense mutation in the HPSE2 gene (613469.0009).
Using antisense morpholinos, Roberts et al. (2014) found that knockdown of Hpse2 in Xenopus embryos interfered with hatching and escape reflexes and caused abnormal development of the gut and tail. Knockdown of Hpse2 also caused meandering of motor nerve paths and axon bundles that were less compact than controls. Biochemical analysis revealed upregulation of Fgf2 and phosphorylated Erk (see 176872) signaling and altered expression of neural- and muscle-associated transcripts.
Guo et al. (2015) found that Hpse2 -/- mice were smaller than wildtype littermates and died within 1 month of birth. Hpse2 -/- mutants had small kidneys, enlarged fibrotic bladders, and abnormally high resting and voiding intravesical pressures. Hpse2 -/- mice also showed reduced intestinal content compared with wildtype, suggesting possible malnutrition and digestive tract defect. Blood chemistry and urinalysis of mutant mice revealed proteinurea due to renal dysfunction, even though their small kidneys appeared grossly normal and had normal total glomeruli counts. Hpse2 -/- cells of all 3 bladder tissue layers (urothelium, lamina propria, detrusor smooth muscle) showed significantly reduced proliferation rates compared with wildtype. Mutant bladders showed aberrant Tgf-beta (TGFB1; 190180) signaling concomitant with abnormal collagen deposition.
In affected individuals from 6 Colombian families with urofacial syndrome (UFS1; 236730), Pang et al. (2010) identified homozygosity for a 1516C-T transition in exon 11 of the HPSE2 gene, resulting in an arg506-to-ter (R506X) substitution predicted to cause a truncated protein lacking 86 C-terminal amino acids.
In affected individuals with urofacial syndrome (UFS1; 236730) from 2 United States pedigrees with a common Irish heritage, Pang et al. (2010) identified homozygosity for a 2-bp deletion (1465delAA) in exon 10 of the HPSE2 gene, predicted to cause a frameshift resulting in a larger protein of 613 amino acids with a completely different sequence for the last 125 residues.
In 2 Irish sisters with urofacial syndrome, originally reported by Garcia-Minaur et al. (2001), Daly et al. (2010) identified homozygosity for the 1465delAA mutation; Daly et al. (2010) predicted that the frameshift would result in nonsense-mediated decay or in a readily-degraded unfolded protein. The sisters had strikingly different presentations: one was severely affected from childhood and underwent multiple urologic surgeries, whereas the other was diagnosed only at age 25 years when she accompanied her sister to the urologic clinic. Their parents were heterozygous for the mutation, which was not found in 96 European controls.
In 2 French brothers with urofacial syndrome (UFS1; 236730), Pang et al. (2010) identified compound heterozygosity for the 2-bp deletion in exon 10 of the HPSE2 gene (613469.0002) and another 2-bp deletion (241delCT) in exon 1.
By copy number analysis in a consanguineous British Pakistani family with urofacial syndrome (UFS1; 236730), Daly et al. (2010) identified homozygosity for an intragenic deletion encompassing exons 8 and 9 of the HPSE2 gene that segregated with the disease. PCR analysis and DNA sequencing across the breakpoints defined a 10.81-kb deletion and a 23-bp insertion at the breakpoints, predicted to cause an in-frame deletion of exons 8 and 9 and removal of 74 amino acids. The unaffected parents were heterozygous for the mutation, which was not found in 93 Pakistani controls.
In a 12-year-old Spanish boy with urofacial syndrome (UFS1; 236730), originally reported by Garcia-Minaur et al. (2001), Daly et al. (2010) identified homozygosity for an in-frame deletion of exon 3 of the HPSE2 gene, resulting in removal of 54 amino acids from the protein. His consanguineous parents were heterozygous for the mutation, which was not found in 96 European controls. His father was reported to have had multiple urinary tract infections, although urologic investigations were normal and he did not show the characteristic grimacing; he died at 65 years of age due to cerebral hemorrhage.
In a 16-year-old Turkish girl with urofacial syndrome (UFS1; 236730), originally reported by Derbent et al. (2009), Daly et al. (2010) identified homozygosity for a 1414C-T transition in exon 10 of the HPSE2 gene, resulting in an arg472-to-ter (R472X) substitution. Her unaffected parents were heterozygous for the mutation, which was not found in 96 Turkish controls.
In 18-month-old Turkish twin brothers with urofacial syndrome (UFS1; 236730), previously reported by Aydogdu et al. (2010), Daly et al. (2010) identified homozygosity for a 457C-T transition in exon 3 of the HPSE2 gene, resulting in an arg153-to-ter (R153X) substitution. Both patients presented with urosepsis and were found to have dysmorphic bladders. Their unaffected parents were heterozygous for the mutation, which was not found in 96 Turkish controls.
In 4 sibs and a cousin from a large Turkish pedigree with urofacial syndrome (UFS1; 236730), previously reported by Aydogdu et al. (2010), Daly et al. (2010) identified homozygosity for a 1-bp insertion (57insC) in exon 1 of the HPSE2 gene, predicted to cause a frameshift and premature stop codon at residue 64. All 4 unaffected parents and 10 unaffected sibs were heterozygous for the mutation, which was not found in 96 Turkish controls.
In 3 sisters, born of first-cousin Pakistani parents, with urofacial syndrome (UFS1; 236730), Mahmood et al. (2012) identified homozygosity for a c.1628A-T transversion in the HPSE2 gene, resulting in an asn543-to-ile (N543I) substitution at a highly conserved residue. The parents and 3 unaffected sibs were heterozygous for the mutation, which was not found in 113 ethnically matched controls.
Aydogdu, O., Burgu, B., Demirel, F., Soygur, T., Ozcakar, Z. B., Yalcinkaya, F., Tekgul, S. Ochoa syndrome: a spectrum of urofacial syndrome. Europ. J. Pediat. 169: 431-435, 2010. [PubMed: 19669792] [Full Text: https://doi.org/10.1007/s00431-009-1042-9]
Daly, S. B., Urquhart, J. E., Hilton, E., McKenzie, E. A., Kammerer, R. A., Lewis, M., Kerr, B., Stuart, H., Donnai, D., Long, D. A., Burgu, B., Aydogdu, O., and 9 others. Mutations in HPSE2 cause urofacial syndrome. Am. J. Hum. Genet. 86: 963-969, 2010. Note: Erratum: Am. J. Hum. Genet. 87: 309 only, 2010. [PubMed: 20560210] [Full Text: https://doi.org/10.1016/j.ajhg.2010.05.006]
de Moura, J. P., Jr., Nicolau, S. M., Stavale, J. N., da Silva Pinhal, M. A., de Matos, L. L., Baracat, E. C., de Lima, G. R. Heparanase-2 expression in normal ovarian epithelium and in benign and malignant ovarian tumors. Int. J. Gynec. Cancer 19: 1494-1500, 2009. [PubMed: 19955924] [Full Text: https://doi.org/10.1111/IGC.0b013e3181a834a2]
Derbent, M., Melek, E., Arman, A., Uckan, S., Baskin, E. Urofacial (Ochoa) syndrome: can a facial gestalt represent severe voiding dysfunction? Renal Failure 31: 589-592, 2009. [PubMed: 19839856] [Full Text: https://doi.org/10.1080/08860220903003370]
Garcia-Minaur, S., Oliver, F., Yanez, J. M., Soriano, J. R., Quinn, F., Reardon, W. Three new European cases of urofacial (Ochoa) syndrome. Clin. Dysmorph. 10: 165-170, 2001. [PubMed: 11446407] [Full Text: https://doi.org/10.1097/00019605-200107000-00002]
Guo, C., Kaneko, S., Sun, Y., Huang, Y., Vlodavsky, I., Li, X., Li, Z.-R., Li, X. A mouse model of urofacial syndrome with dysfunctional urination. Hum. Molec. Genet. 24: 1991-1999, 2015. [PubMed: 25510506] [Full Text: https://doi.org/10.1093/hmg/ddu613]
Mahmood, S., Beetz, C., Tahir, M. M., Imran, M., Mumtaz, R., Bassmann, I., Jahic, A., Malik, M., Nurnberg, G., Hassan, S. A. A., Rana, S., Nurnberg, P., Hubner, C. A. First missense mutation in urofacial syndrome. Clin. Genet. 81: 88-92, 2012. [PubMed: 21332471] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01649.x]
McKenzie, E., Tyson, K., Stamps, A., Smith, P., Turner, P., Barry, R., Hircock, M., Patel, S., Barry, E., Stubberfield, C., Terrett, J., Page, M. Cloning and expression profiling of Hpa2, a novel mammalian heparanase family member. Biochem. Biophys. Res. Commun. 276: 1170-1177, 2000. [PubMed: 11027606] [Full Text: https://doi.org/10.1006/bbrc.2000.3586]
Pang, J., Zhang, S., Yang, P., Hawkins-Lee, B., Zhong, J., Zhang, Y., Ochoa, B., Agundez, J. A. G., Voelckel, M.-A., Fisher, R. B., Gu, W., Xiong, W.-C., Mei, L., She, J.-X., Wang, C.-Y. Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial syndrome. Am. J. Hum. Genet. 86: 957-962, 2010. Note: Erratum: Am. J. Hum. Genet. 87: 161 only, 2010. [PubMed: 20560209] [Full Text: https://doi.org/10.1016/j.ajhg.2010.04.016]
Roberts, N. A., Woolf, A. S., Stuart, H. M., Thuret, R., McKenzie, E. A., Newman, W. G., Hilton, E. N. Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus. Hum. Molec. Genet. 23: 4302-4314, 2014. [PubMed: 24691552] [Full Text: https://doi.org/10.1093/hmg/ddu147]