Cargando…

Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle

BACKGROUND: Inherited epidermolysis bullosa (EB) is a group of painful and life-threatening genetic disorders that are characterized by mechanically induced blistering of the skin and mucous membranes. Congenital skin fragility resembling EB was recently reported in three Charolais calves born in tw...

Descripción completa

Detalles Bibliográficos
Autores principales: Boussaha, Mekki, Boulling, Arnaud, Wolgust, Valérie, Bourgeois-Brunel, Lorraine, Michot, Pauline, Grohs, Cécile, Gaiani, Nicolas, Grivaud, Pierre-Yves, Leclerc, Hélène, Danchin-Burge, Coralie, Vilotte, Marthe, Rivière, Julie, Boichard, Didier, Gourreau, Jean-Marie, Capitan, Aurélien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258996/
https://www.ncbi.nlm.nih.gov/pubmed/37308849
http://dx.doi.org/10.1186/s12711-023-00814-1
_version_ 1785057573728157696
author Boussaha, Mekki
Boulling, Arnaud
Wolgust, Valérie
Bourgeois-Brunel, Lorraine
Michot, Pauline
Grohs, Cécile
Gaiani, Nicolas
Grivaud, Pierre-Yves
Leclerc, Hélène
Danchin-Burge, Coralie
Vilotte, Marthe
Rivière, Julie
Boichard, Didier
Gourreau, Jean-Marie
Capitan, Aurélien
author_facet Boussaha, Mekki
Boulling, Arnaud
Wolgust, Valérie
Bourgeois-Brunel, Lorraine
Michot, Pauline
Grohs, Cécile
Gaiani, Nicolas
Grivaud, Pierre-Yves
Leclerc, Hélène
Danchin-Burge, Coralie
Vilotte, Marthe
Rivière, Julie
Boichard, Didier
Gourreau, Jean-Marie
Capitan, Aurélien
author_sort Boussaha, Mekki
collection PubMed
description BACKGROUND: Inherited epidermolysis bullosa (EB) is a group of painful and life-threatening genetic disorders that are characterized by mechanically induced blistering of the skin and mucous membranes. Congenital skin fragility resembling EB was recently reported in three Charolais calves born in two distinct herds from unaffected parents. Phenotypic and genetic analyses were carried out to describe this condition and its molecular etiology. RESULTS: Genealogical, pathological and histological investigations confirmed the diagnosis of recessive EB. However, the affected calves showed milder clinical signs compared to another form of EB, which was previously reported in the same breed and is caused by a homozygous deletion of the ITGB4 gene. Homozygosity mapping followed by analysis of the whole-genome sequences of two cases and 5031 control individuals enabled us to prioritize a splice donor site of ITGA6 (c.2160 + 1G > T; Chr2 g.24112740C > A) as the most compelling candidate variant. This substitution showed a perfect genotype–phenotype correlation in the two affected pedigrees and was found to segregate only in Charolais, and at a very low frequency (f = 1.6 × 10(−4)) after genotyping 186,154 animals from 15 breeds. Finally, RT-PCR analyses revealed increased retention of introns 14 and 15 of the ITGA6 gene in a heterozygous mutant cow compared with a matched control. The mutant mRNA is predicted to cause a frameshift (ITGA6 p.I657Mfs1) that affects the assembly of the integrin α6β4 dimer and its correct anchoring to the cell membrane. This dimer is a key component of the hemidesmosome anchoring complex, which ensures the attachment of basal epithelial cells to the basal membrane. Based on these elements, we arrived at a diagnosis of junctional EB. CONCLUSIONS: We report a rare example of partial phenocopies observed in the same breed and due to mutations that affect two members of the same protein dimer, and provide the first evidence of an ITGA6 mutation that causes EB in livestock species. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12711-023-00814-1.
format Online
Article
Text
id pubmed-10258996
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-102589962023-06-13 Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle Boussaha, Mekki Boulling, Arnaud Wolgust, Valérie Bourgeois-Brunel, Lorraine Michot, Pauline Grohs, Cécile Gaiani, Nicolas Grivaud, Pierre-Yves Leclerc, Hélène Danchin-Burge, Coralie Vilotte, Marthe Rivière, Julie Boichard, Didier Gourreau, Jean-Marie Capitan, Aurélien Genet Sel Evol Short Communication BACKGROUND: Inherited epidermolysis bullosa (EB) is a group of painful and life-threatening genetic disorders that are characterized by mechanically induced blistering of the skin and mucous membranes. Congenital skin fragility resembling EB was recently reported in three Charolais calves born in two distinct herds from unaffected parents. Phenotypic and genetic analyses were carried out to describe this condition and its molecular etiology. RESULTS: Genealogical, pathological and histological investigations confirmed the diagnosis of recessive EB. However, the affected calves showed milder clinical signs compared to another form of EB, which was previously reported in the same breed and is caused by a homozygous deletion of the ITGB4 gene. Homozygosity mapping followed by analysis of the whole-genome sequences of two cases and 5031 control individuals enabled us to prioritize a splice donor site of ITGA6 (c.2160 + 1G > T; Chr2 g.24112740C > A) as the most compelling candidate variant. This substitution showed a perfect genotype–phenotype correlation in the two affected pedigrees and was found to segregate only in Charolais, and at a very low frequency (f = 1.6 × 10(−4)) after genotyping 186,154 animals from 15 breeds. Finally, RT-PCR analyses revealed increased retention of introns 14 and 15 of the ITGA6 gene in a heterozygous mutant cow compared with a matched control. The mutant mRNA is predicted to cause a frameshift (ITGA6 p.I657Mfs1) that affects the assembly of the integrin α6β4 dimer and its correct anchoring to the cell membrane. This dimer is a key component of the hemidesmosome anchoring complex, which ensures the attachment of basal epithelial cells to the basal membrane. Based on these elements, we arrived at a diagnosis of junctional EB. CONCLUSIONS: We report a rare example of partial phenocopies observed in the same breed and due to mutations that affect two members of the same protein dimer, and provide the first evidence of an ITGA6 mutation that causes EB in livestock species. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12711-023-00814-1. BioMed Central 2023-06-12 /pmc/articles/PMC10258996/ /pubmed/37308849 http://dx.doi.org/10.1186/s12711-023-00814-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Short Communication
Boussaha, Mekki
Boulling, Arnaud
Wolgust, Valérie
Bourgeois-Brunel, Lorraine
Michot, Pauline
Grohs, Cécile
Gaiani, Nicolas
Grivaud, Pierre-Yves
Leclerc, Hélène
Danchin-Burge, Coralie
Vilotte, Marthe
Rivière, Julie
Boichard, Didier
Gourreau, Jean-Marie
Capitan, Aurélien
Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle
title Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle
title_full Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle
title_fullStr Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle
title_full_unstemmed Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle
title_short Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle
title_sort integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in charolais cattle
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258996/
https://www.ncbi.nlm.nih.gov/pubmed/37308849
http://dx.doi.org/10.1186/s12711-023-00814-1
work_keys_str_mv AT boussahamekki integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT boullingarnaud integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT wolgustvalerie integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT bourgeoisbrunellorraine integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT michotpauline integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT grohscecile integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT gaianinicolas integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT grivaudpierreyves integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT leclerchelene integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT danchinburgecoralie integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT vilottemarthe integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT rivierejulie integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT boicharddidier integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT gourreaujeanmarie integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle
AT capitanaurelien integrinalpha6homozygoussplicesitemutationcausesanewformofjunctionalepidermolysisbullosaincharolaiscattle