Beaman, Glenda M. and Lopes, Filipa M. and Hofmann, Aybike and Roesch, Wolfgang and Promm, Martin and Bijlsma, Emilia K. and Patel, Chirag and Akinci, Aykut and Burgu, Berk and Knijnenburg, Jeroen and Ho, Gladys and Aufschlaeger, Christina and Dathe, Sylvia and Voelckel, Marie Antoinette and Cohen, Monika and Yue, Wyatt W. and Stuart, Helen M. and Mckenzie, Edward A. and Elvin, Mark and Roberts, Neil A. and Woolf, Adrian S. and Newman, William G. (2022) Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder. FRONTIERS IN GENETICS, 13: 896125. ISSN , 1664-8021
Full text not available from this repository. (Request a copy)Abstract
Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2, coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T>A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C>G variant encoding the missense p.Pro140Arg in trans with c.1099-1G>A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | JOINT CONSENSUS RECOMMENDATION; HEPARANASE 2; MEDICAL GENETICS; AMERICAN-COLLEGE; OCHOA-SYNDROME; GENOMICS; CHILD; HPA2; TRIPLICATION; EXPRESSION; HPSE2; urofacial; heparanase-2; LRIG2; missense; Ochoa syndrome; triplication; rare disease |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Urologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Dec 2023 07:29 |
| Last Modified: | 13 Dec 2023 07:29 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58724 |
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