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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-9259970 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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