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

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...

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Autores principales: Beaman, Glenda M., Lopes, Filipa M., Hofmann, Aybike, Roesch, Wolfgang, Promm, Martin, Bijlsma, Emilia K., Patel, Chirag, Akinci, Aykut, Burgu, Berk, Knijnenburg, Jeroen, Ho, Gladys, Aufschlaeger, Christina, Dathe, Sylvia, Voelckel, Marie Antoinette, Cohen, Monika, Yue, Wyatt W., Stuart, Helen M., Mckenzie, Edward A., Elvin, Mark, Roberts, Neil A., Woolf, Adrian S., Newman, William G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259970/
https://www.ncbi.nlm.nih.gov/pubmed/35812751
http://dx.doi.org/10.3389/fgene.2022.896125
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author Beaman, Glenda M.
Lopes, Filipa M.
Hofmann, Aybike
Roesch, Wolfgang
Promm, Martin
Bijlsma, Emilia K.
Patel, Chirag
Akinci, Aykut
Burgu, Berk
Knijnenburg, Jeroen
Ho, Gladys
Aufschlaeger, Christina
Dathe, Sylvia
Voelckel, Marie Antoinette
Cohen, Monika
Yue, Wyatt W.
Stuart, Helen M.
Mckenzie, Edward A.
Elvin, Mark
Roberts, Neil A.
Woolf, Adrian S.
Newman, William G.
author_facet Beaman, Glenda M.
Lopes, Filipa M.
Hofmann, Aybike
Roesch, Wolfgang
Promm, Martin
Bijlsma, Emilia K.
Patel, Chirag
Akinci, Aykut
Burgu, Berk
Knijnenburg, Jeroen
Ho, Gladys
Aufschlaeger, Christina
Dathe, Sylvia
Voelckel, Marie Antoinette
Cohen, Monika
Yue, Wyatt W.
Stuart, Helen M.
Mckenzie, Edward A.
Elvin, Mark
Roberts, Neil A.
Woolf, Adrian S.
Newman, William G.
author_sort Beaman, Glenda M.
collection PubMed
description 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.
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spelling pubmed-92599702022-07-08 Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder Beaman, Glenda M. Lopes, Filipa M. Hofmann, Aybike Roesch, Wolfgang Promm, Martin Bijlsma, Emilia K. Patel, Chirag Akinci, Aykut Burgu, Berk Knijnenburg, Jeroen Ho, Gladys Aufschlaeger, Christina Dathe, Sylvia Voelckel, Marie Antoinette Cohen, Monika Yue, Wyatt W. Stuart, Helen M. Mckenzie, Edward A. Elvin, Mark Roberts, Neil A. Woolf, Adrian S. Newman, William G. Front Genet Genetics 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. Frontiers Media S.A. 2022-06-23 /pmc/articles/PMC9259970/ /pubmed/35812751 http://dx.doi.org/10.3389/fgene.2022.896125 Text en 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. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Beaman, Glenda M.
Lopes, Filipa M.
Hofmann, Aybike
Roesch, Wolfgang
Promm, Martin
Bijlsma, Emilia K.
Patel, Chirag
Akinci, Aykut
Burgu, Berk
Knijnenburg, Jeroen
Ho, Gladys
Aufschlaeger, Christina
Dathe, Sylvia
Voelckel, Marie Antoinette
Cohen, Monika
Yue, Wyatt W.
Stuart, Helen M.
Mckenzie, Edward A.
Elvin, Mark
Roberts, Neil A.
Woolf, Adrian S.
Newman, William G.
Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder
title Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder
title_full Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder
title_fullStr Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder
title_full_unstemmed Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder
title_short Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder
title_sort expanding the hpse2 genotypic spectrum in urofacial syndrome, a disease featuring a peripheral neuropathy of the urinary bladder
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259970/
https://www.ncbi.nlm.nih.gov/pubmed/35812751
http://dx.doi.org/10.3389/fgene.2022.896125
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