A de novo mutation in <scp><i>KRT5</i></scp> in a crossbred calf with epidermolysis bullosa simplex

Jacinto, Joana G. P.; Häfliger, Irene M.; Veiga, Inês Berenguer; Drögemüller, Cord; Agerholm, Jørgen Steen

doi:10.1111/jvim.15943

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…In contrast to humans, where more than 1000 variants in at least 16 genes have been associated with EB [1], molecular studies are rarely reported in domestic animals. EBS was associated with variants in PLEC in a litter of dogs [15], KRT5 in cattle [16,17] and a dog [18], and KRT14 in a cat [19]. DEB was associated with variants in COL7A1 in cattle [20] and dogs [21].…”

Section: Introductionmentioning

confidence: 99%

Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa

Kiener,

Troyer,

Ruvolo

et al. 2023

Genes

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Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals. We investigated two unrelated cats with recurring erosions and ulcers on ear pinnae, oral mucosa, and paw pads that were suggestive of EB. Histopathology confirmed the diagnosis of EB in both cats. Case 1 was severe and had to be euthanized at 5 months of age. Case 2 had a milder course and was alive at 11 years of age at the time of writing. Whole genome sequencing of both affected cats revealed independent homozygous variants in COL17A1 encoding the collagen type XVII alpha 1 chain. Loss of function variants in COL17A1 lead to junctional epidermolysis bullosa (JEB) in human patients. The identified splice site variant in case 1, c.3019+1del, was predicted to lead to a complete deficiency in collagen type XVII. Case 2 had a splice region variant, c.769+5G>A. Assessment of the functional impact of this variant on the transcript level demonstrated partial aberrant splicing with residual expression of wildtype transcript. Thus, the molecular analyses provided a plausible explanation of the difference in clinical severity between the two cases and allowed the refinement of the diagnosis in the affected cats to JEB. This study highlights the complexity of EB in animals and contributes to a better understanding of the genotype-phenotype correlation in COL17A1-related JEB.

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Section: Introductionmentioning

confidence: 99%

Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa

Kiener,

Troyer,

Ruvolo

et al. 2023

Genes

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Naturally occurring genetic diseases caused by de novo variants in domestic animals

Azevedo,

Amaro,

Niza‐Ribeiro

et al. 2024

Animal Genetics

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With the advent of next‐generation sequencing, an increasing number of cases of de novo variants in domestic animals have been reported in scientific literature primarily associated with clinically severe phenotypes. The emergence of new variants at each generation is a crucial aspect in understanding the pathology of early‐onset diseases in animals and can provide valuable insights into similar diseases in humans. With the aim of collecting deleterious de novo variants in domestic animals, we searched the scientific literature and compiled reports on 42 de novo variants in 31 genes in domestic animals. No clear disease‐associated phenotype has been established in humans for three of these genes (NUMB, ANKRD28 and KCNG1). For the remaining 28 genes, a strong similarity between animal and human phenotypes was recognized from available information in OMIM and OMIA, revealing the importance of comparative studies and supporting the use of domestic animals as natural models for human diseases, in line with the One Health approach.

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DSP missense variant in a Scottish Highland calf with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects

et al. 2022

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Background Ichthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive stratum corneum with the formation of more or less adherent scales. Ichthyosis affects humans and animals. Two rare bovine forms are reported, the severe harlequin ichthyosis and the less severe congenital ichthyosis, both characterized by a severe orthokeratotic lamellar hyperkeratosis. Results A 2-weeks-old purebred Scottish Highland calf was referred because of a syndrome resembling congenital ichthyosis. The clinical phenotype included diffuse alopecia and a markedly lichenified skin covered with large and excessive scales. Additionally, conjunctivitis and ulceration of the cornea were noted. Post-mortem examination revealed deep fissures in the diffusely thickened tongue and histopathological findings in the skin confirmed the clinical diagnosis. Whole-genome sequencing of the affected calf and comparison of the data with control genomes was performed. A search for private variants in known candidate genes for skin phenotypes including genes related with erosive and hyperkeratotic lesions revealed a single homozygous protein-changing variant, DSP: c.6893 C>A, or p.Ala2298Asp. The variant is predicted to change a highly conserved residue in the C-terminal plakin domain of the desmoplakin protein, which represents a main intracellular component of desmosomes, important intercellular adhesion molecules in various tissues including epidermis. Sanger sequencing confirmed the variant was homozygous in the affected calf and heterozygous in both parents. Further genotyping of 257 Scottish Highland animals from Switzerland revealed an estimated allele frequency of 1.2%. The mutant allele was absent in more than 4800 controls from various other cattle breeds. Conclusions This study represents the first report of combined lesions compatible with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects associated with a DSP missense variant as the most likely underlying cause. To the best of our knowledge, this study is also the first report of a DSP-related syndromic form of congenital ichthyosis in domestic animals. The results of our study enable genetic testing to avoid the unintentional occurrence of further affected cattle. The findings were added to the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002243-9913).

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A de novo mutation in KRT5 in a crossbred calf with epidermolysis bullosa simplex

Cited by 3 publications

References 47 publications

Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa

Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa

Naturally occurring genetic diseases caused by de novo variants in domestic animals

DSP missense variant in a Scottish Highland calf with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects

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