Cargando…

LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa

In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the baseme...

Descripción completa

Detalles Bibliográficos
Autores principales: Kiener, Sarah, Laprais, Aurore, Mauldin, Elizabeth A., Jagannathan, Vidhya, Olivry, Thierry, Leeb, Tosso
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565164/
https://www.ncbi.nlm.nih.gov/pubmed/32906717
http://dx.doi.org/10.3390/genes11091055
_version_ 1783595875645259776
author Kiener, Sarah
Laprais, Aurore
Mauldin, Elizabeth A.
Jagannathan, Vidhya
Olivry, Thierry
Leeb, Tosso
author_facet Kiener, Sarah
Laprais, Aurore
Mauldin, Elizabeth A.
Jagannathan, Vidhya
Olivry, Thierry
Leeb, Tosso
author_sort Kiener, Sarah
collection PubMed
description In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals.
format Online
Article
Text
id pubmed-7565164
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-75651642020-10-26 LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa Kiener, Sarah Laprais, Aurore Mauldin, Elizabeth A. Jagannathan, Vidhya Olivry, Thierry Leeb, Tosso Genes (Basel) Article In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals. MDPI 2020-09-07 /pmc/articles/PMC7565164/ /pubmed/32906717 http://dx.doi.org/10.3390/genes11091055 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kiener, Sarah
Laprais, Aurore
Mauldin, Elizabeth A.
Jagannathan, Vidhya
Olivry, Thierry
Leeb, Tosso
LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa
title LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa
title_full LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa
title_fullStr LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa
title_full_unstemmed LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa
title_short LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa
title_sort lamb3 missense variant in australian shepherd dogs with junctional epidermolysis bullosa
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565164/
https://www.ncbi.nlm.nih.gov/pubmed/32906717
http://dx.doi.org/10.3390/genes11091055
work_keys_str_mv AT kienersarah lamb3missensevariantinaustralianshepherddogswithjunctionalepidermolysisbullosa
AT lapraisaurore lamb3missensevariantinaustralianshepherddogswithjunctionalepidermolysisbullosa
AT mauldinelizabetha lamb3missensevariantinaustralianshepherddogswithjunctionalepidermolysisbullosa
AT jagannathanvidhya lamb3missensevariantinaustralianshepherddogswithjunctionalepidermolysisbullosa
AT olivrythierry lamb3missensevariantinaustralianshepherddogswithjunctionalepidermolysisbullosa
AT leebtosso lamb3missensevariantinaustralianshepherddogswithjunctionalepidermolysisbullosa