Cargando…

A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome

SIMPLE SUMMARY: Genodermatoses represent inherited disorders of the skin that mostly follow a monogenic mode of inheritance. Heritable connective tissue disorders such as classical Ehlers–Danlos syndrome (cEDS) belong to this group of human rare diseases that sporadically occur in other species. Her...

Descripción completa

Detalles Bibliográficos
Autores principales: Jacinto, Joana G. P., Häfliger, Irene M., Veiga, Inês M. B., Letko, Anna, Benazzi, Cinzia, Bolcato, Marilena, Drögemüller, Cord
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692662/
https://www.ncbi.nlm.nih.gov/pubmed/33143196
http://dx.doi.org/10.3390/ani10112002
_version_ 1783614564316741632
author Jacinto, Joana G. P.
Häfliger, Irene M.
Veiga, Inês M. B.
Letko, Anna
Benazzi, Cinzia
Bolcato, Marilena
Drögemüller, Cord
author_facet Jacinto, Joana G. P.
Häfliger, Irene M.
Veiga, Inês M. B.
Letko, Anna
Benazzi, Cinzia
Bolcato, Marilena
Drögemüller, Cord
author_sort Jacinto, Joana G. P.
collection PubMed
description SIMPLE SUMMARY: Genodermatoses represent inherited disorders of the skin that mostly follow a monogenic mode of inheritance. Heritable connective tissue disorders such as classical Ehlers–Danlos syndrome (cEDS) belong to this group of human rare diseases that sporadically occur in other species. Herein, affected cattle are reported showing skin lesions including cutis laxa clinically and pathologically resembling cEDS in humans. Microscopic findings in the deeper dermis were consistent with collagen dysplasia. Whole-genome sequencing (WGS) identified a most likely disease-causing mutation in the COL5A2 gene. The COL5A2 gene is known to be associated with dominant inherited cEDS forms in mice and humans, but so far, it was not shown to cause a similar phenotype in domestic animals. The disease phenotype examined herein showed co-segregation with the identified missense variant within the maternal line across two generations and is most likely due to a spontaneous mutation event. Rare non-lethal disorders such as cEDS in livestock are mostly not diagnosed, but might affect animal welfare and thus lower the value of affected animals. WGS-based precision diagnostics allows understanding rare disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders. ABSTRACT: Classical Ehlers–Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by variable degrees of skin hyperextensibility and fragility, atrophic scarring, and generalized joint hypermobility. The purpose of this study was to characterize the clinicopathological phenotype of a cEDS-affected Holstein calf and to identify the causative genetic variant associated with the disorder by whole-genome sequencing (WGS). A 3-day-old female Holstein calf was referred because of easily induced skin detachment and hyperextensibility in the neck. A complete clinical investigation was performed in the calf, dam, and maternal-grandmother. The calf and dam showed hyperextensibility of the neck skin and atrophic scarring; additionally, the calf presented skin fragility. Moreover, the histopathology of biopsies from the calf and its dam showed that the collagen bundles in affected skin areas were wavy, short, thin, and surrounded by edema and moderate to severe acute hemorrhages. Genetic analysis revealed a private heterozygous missense variant in COL5A2 (c.2366G>T; p.Gly789Val) that was present only in the calf and dam. This confirmed the diagnosis of cEDS and represents the first report of a causal variant for cEDS in cattle and the first COL5A2-related large animal model.
format Online
Article
Text
id pubmed-7692662
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-76926622020-11-28 A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome Jacinto, Joana G. P. Häfliger, Irene M. Veiga, Inês M. B. Letko, Anna Benazzi, Cinzia Bolcato, Marilena Drögemüller, Cord Animals (Basel) Article SIMPLE SUMMARY: Genodermatoses represent inherited disorders of the skin that mostly follow a monogenic mode of inheritance. Heritable connective tissue disorders such as classical Ehlers–Danlos syndrome (cEDS) belong to this group of human rare diseases that sporadically occur in other species. Herein, affected cattle are reported showing skin lesions including cutis laxa clinically and pathologically resembling cEDS in humans. Microscopic findings in the deeper dermis were consistent with collagen dysplasia. Whole-genome sequencing (WGS) identified a most likely disease-causing mutation in the COL5A2 gene. The COL5A2 gene is known to be associated with dominant inherited cEDS forms in mice and humans, but so far, it was not shown to cause a similar phenotype in domestic animals. The disease phenotype examined herein showed co-segregation with the identified missense variant within the maternal line across two generations and is most likely due to a spontaneous mutation event. Rare non-lethal disorders such as cEDS in livestock are mostly not diagnosed, but might affect animal welfare and thus lower the value of affected animals. WGS-based precision diagnostics allows understanding rare disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders. ABSTRACT: Classical Ehlers–Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by variable degrees of skin hyperextensibility and fragility, atrophic scarring, and generalized joint hypermobility. The purpose of this study was to characterize the clinicopathological phenotype of a cEDS-affected Holstein calf and to identify the causative genetic variant associated with the disorder by whole-genome sequencing (WGS). A 3-day-old female Holstein calf was referred because of easily induced skin detachment and hyperextensibility in the neck. A complete clinical investigation was performed in the calf, dam, and maternal-grandmother. The calf and dam showed hyperextensibility of the neck skin and atrophic scarring; additionally, the calf presented skin fragility. Moreover, the histopathology of biopsies from the calf and its dam showed that the collagen bundles in affected skin areas were wavy, short, thin, and surrounded by edema and moderate to severe acute hemorrhages. Genetic analysis revealed a private heterozygous missense variant in COL5A2 (c.2366G>T; p.Gly789Val) that was present only in the calf and dam. This confirmed the diagnosis of cEDS and represents the first report of a causal variant for cEDS in cattle and the first COL5A2-related large animal model. MDPI 2020-10-30 /pmc/articles/PMC7692662/ /pubmed/33143196 http://dx.doi.org/10.3390/ani10112002 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
Jacinto, Joana G. P.
Häfliger, Irene M.
Veiga, Inês M. B.
Letko, Anna
Benazzi, Cinzia
Bolcato, Marilena
Drögemüller, Cord
A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome
title A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome
title_full A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome
title_fullStr A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome
title_full_unstemmed A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome
title_short A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome
title_sort heterozygous missense variant in the col5a2 in holstein cattle resembling the classical ehlers–danlos syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692662/
https://www.ncbi.nlm.nih.gov/pubmed/33143196
http://dx.doi.org/10.3390/ani10112002
work_keys_str_mv AT jacintojoanagp aheterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT hafligerirenem aheterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT veigainesmb aheterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT letkoanna aheterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT benazzicinzia aheterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT bolcatomarilena aheterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT drogemullercord aheterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT jacintojoanagp heterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT hafligerirenem heterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT veigainesmb heterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT letkoanna heterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT benazzicinzia heterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT bolcatomarilena heterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome
AT drogemullercord heterozygousmissensevariantinthecol5a2inholsteincattleresemblingtheclassicalehlersdanlossyndrome