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Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder

Lookup NU author(s): Professor Wyatt YueORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Copyright © 2022 Beaman, Lopes, Hofmann, Roesch, Promm, Bijlsma, Patel, Akinci, Burgu, Knijnenburg, Ho, Aufschlaeger, Dathe, Voelckel, Cohen, Yue, Stuart, Mckenzie, Elvin, Roberts, Woolf and Newman. 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.


Publication metadata

Author(s): Beaman GM, Lopes FM, Hofmann A, Roesch W, Promm M, Bijlsma EK, Patel C, Akinci A, Burgu B, Knijnenburg J, Ho G, Aufschlaeger C, Dathe S, Voelckel MA, Cohen M, Yue WW, Stuart HM, Mckenzie EA, Elvin M, Roberts NA, Woolf AS, Newman WG

Publication type: Article

Publication status: Published

Journal: Frontiers in Genetics

Year: 2022

Volume: 13

Online publication date: 23/06/2022

Acceptance date: 23/05/2022

Date deposited: 12/09/2024

ISSN (electronic): 1664-8021

Publisher: Frontiers Media S.A.

URL: https://doi.org/10.3389/fgene.2022.896125

DOI: 10.3389/fgene.2022.896125

Data Access Statement: The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors. The data presented in the study are deposited in the CLINVAR repository, accession numbers SCV002525226-SCV002525230.


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Funding

Funder referenceFunder name
Medical Research Council (project grant MR/L002744/1)
Kidney Research United Kingdom (project grant Paed_RP_002_20190925)
Kidney Research United Kingdom (project grant Paed_RP_005_20190925)
Kidneys for Life (start-up grant 2018)
KUNO Foundation Regensburg
Manchester NIHR BRC (IS-BRC-1215-20007)
Medical Research Council (project grant MR/T016809/1)
Newlife Foundation (project grants 15-15/03 and 15-16/06)
NIHR Academic Lecturer scheme

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