Abstract:Epidermolysis bullosa (EB) is a hereditary mechanobullous disease of animals and humans, characterized by an extreme fragility of the skin and mucous membranes. The main feature of EB in humans and animals is the formation of blisters and erosions in response to minor mechanical trauma. Epidermolysis bullosa is caused by mutations in the genes that code for structural proteins of the cytoskeleton of the basal keratinocytes or of the basement membrane zone. Based on the ultrastructural levels of tissue separati… Show more
“…Since pathological and histological data were not available, a more precise classification of the disease was not possible [25]. All calves were euthanized shortly after birth by accredited veterinarians because of poor prognosis and with no prospect of improvement [17]. Breeding consultants collected ear tissue samples for genetic analyses from two affected calves.Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Epidermolysis bullosa (EB) is an inherited disorder of the connective tissue that had been observed in many species including cattle [17]. Affected individuals suffer from skin blisters and high skin fragility because of impaired adherence of the epidermis to the underlying dermis [17].…”
Section: Introductionmentioning
confidence: 99%
“…Affected individuals suffer from skin blisters and high skin fragility because of impaired adherence of the epidermis to the underlying dermis [17]. There is no cure for EB.…”
BackgroundThe widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions. Inadvertent matings between unnoticed carriers of deleterious alleles may result in the manifestation of fatal phenotypes in their progeny. Breeding consultants and farmers reported on Vorderwald calves with a congenital skin disease. The clinical findings in affected calves were compatible with epidermolysis bullosa.ResultsPedigree analysis indicated autosomal recessive inheritance of epidermolysis bullosa in Vorderwald cattle. We genotyped two diseased and 41 healthy animals at 41,436 single nucleotide polymorphisms and performed whole-genome haplotype-based association testing, which allowed us to map the locus responsible for the skin disease to the distal end of bovine chromosome 22 (P = 8.0 × 10−14). The analysis of whole-genome re-sequencing data of one diseased calf, three obligate mutation carriers and 1682 healthy animals from various bovine breeds revealed a nonsense mutation (rs876174537, p.Arg1588X) in the COL7A1 gene that segregates with the disease. The same mutation was previously detected in three calves with dystrophic epidermolysis bullosa from the Rotes Höhenvieh cattle breed. We show that diseased animals from Vorderwald and Rotes Höhenvieh cattle are identical by descent for an 8.72 Mb haplotype encompassing rs876174537 indicating they inherited the deleterious allele from a recent common ancestor.ConclusionsAutosomal recessive epidermolysis bullosa in Vorderwald and Rotes Höhenvieh cattle is caused by a nonsense mutation in the COL7A1 gene. Our findings demonstrate that deleterious alleles may segregate across cattle populations without apparent admixture. The identification of the causal mutation now enables the reliable detection of carrier animals. Genome-based mating strategies can avoid inadvertent matings of carrier animals thereby preventing the birth of homozygous calves that suffer from a painful skin disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0458-2) contains supplementary material, which is available to authorized users.
“…Since pathological and histological data were not available, a more precise classification of the disease was not possible [25]. All calves were euthanized shortly after birth by accredited veterinarians because of poor prognosis and with no prospect of improvement [17]. Breeding consultants collected ear tissue samples for genetic analyses from two affected calves.Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Epidermolysis bullosa (EB) is an inherited disorder of the connective tissue that had been observed in many species including cattle [17]. Affected individuals suffer from skin blisters and high skin fragility because of impaired adherence of the epidermis to the underlying dermis [17].…”
Section: Introductionmentioning
confidence: 99%
“…Affected individuals suffer from skin blisters and high skin fragility because of impaired adherence of the epidermis to the underlying dermis [17]. There is no cure for EB.…”
BackgroundThe widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions. Inadvertent matings between unnoticed carriers of deleterious alleles may result in the manifestation of fatal phenotypes in their progeny. Breeding consultants and farmers reported on Vorderwald calves with a congenital skin disease. The clinical findings in affected calves were compatible with epidermolysis bullosa.ResultsPedigree analysis indicated autosomal recessive inheritance of epidermolysis bullosa in Vorderwald cattle. We genotyped two diseased and 41 healthy animals at 41,436 single nucleotide polymorphisms and performed whole-genome haplotype-based association testing, which allowed us to map the locus responsible for the skin disease to the distal end of bovine chromosome 22 (P = 8.0 × 10−14). The analysis of whole-genome re-sequencing data of one diseased calf, three obligate mutation carriers and 1682 healthy animals from various bovine breeds revealed a nonsense mutation (rs876174537, p.Arg1588X) in the COL7A1 gene that segregates with the disease. The same mutation was previously detected in three calves with dystrophic epidermolysis bullosa from the Rotes Höhenvieh cattle breed. We show that diseased animals from Vorderwald and Rotes Höhenvieh cattle are identical by descent for an 8.72 Mb haplotype encompassing rs876174537 indicating they inherited the deleterious allele from a recent common ancestor.ConclusionsAutosomal recessive epidermolysis bullosa in Vorderwald and Rotes Höhenvieh cattle is caused by a nonsense mutation in the COL7A1 gene. Our findings demonstrate that deleterious alleles may segregate across cattle populations without apparent admixture. The identification of the causal mutation now enables the reliable detection of carrier animals. Genome-based mating strategies can avoid inadvertent matings of carrier animals thereby preventing the birth of homozygous calves that suffer from a painful skin disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0458-2) contains supplementary material, which is available to authorized users.
“…To date, defects in four of them have been linked to different types of canine EB: a premature stop codon in PKP1 causing ectodermal dysplasia-skin fragility syndrome [5], a nonsense mutation in PLEC causing EBS [6], an insertion in LAMA3 causing JEB [7] and a missense mutation in COL7A1 causing a mild form of DEB [8]. Additional EB cases with unknown molecular background have been described in German Shorthaired Pointers and mixed-breed dogs with JEB as well as in Akita Inu with DEB [9]. We describe here a novel recessive and severe form of dystrophic EB in Central Asian Shepherd (CAS) dogs with a nonsense variant in COL7A1 .…”
A rare hereditary mechanobullous disorder called epidermolysis bullosa (EB) causes blistering in the skin and the mucosal membranes. To date, nineteen EB-related genes have been discovered in human and other species. We describe here a novel EB variant in dogs. Two newborn littermates of Central Asian Shepherd dogs with severe signs of skin blistering were brought to a veterinary clinic and euthanized due to poor prognosis. In post-mortem examination, the puppies were shown to have findings in the skin and the mucosal membranes characteristic of EB. A whole-genome sequencing of one of the affected puppies was performed to identify the genetic cause. The resequencing data were filtered under a recessive model against variants from 31 other dog genomes, revealing a homozygous case-specific nonsense variant in one of the known EB-causing genes, COL7A1 (c.4579C>T, p.R1527*). The variant results in a premature stop codon and likely absence of the functional protein in the basement membrane of the skin in the affected dogs. This was confirmed by immunohistochemistry using a COL7A1 antibody. Additional screening of the variant indicated full penetrance and breed specificity at ~28% carrier frequency. In summary, this study reveals a novel COL7A1 variant causing recessive dystrophic EB and provides a genetic test for the eradication of the disease from the breed.
“…5,7,8 In basal keratinocytes, plectin and BPAG1e are the main components of the inner plaque of hemidesmosomes. Although all major forms of EB have been identified in domestic animals, 9 this study documents the first spontaneous EBS associated with deleterious variant of plectin.…”
Background-Plectin, a large linker protein found in many tissues, acts to connect components of the cytoskeleton to each other. In the epidermis, plectin binds keratin intermediate filaments to hemidesmosomes. A deficiency of plectin in the skin leads to blister formation in the basal layer and the disease epidermolysis bullosa simplex (EBS).
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