Exonization of a LINE1 fragment implicated in X-linked hypohidrotic ectodermal dysplasia in cattle

Karlskov-Mortensen, Peter; Cirera, Susanna; Nielsen, Ole Lerberg; Arnbjerg, J.; Reibel, J.; Fredholm, Merete; Agerholm, Jørgen Steen

doi:10.1111/j.1365-2052.2011.02192.x

Cited by 16 publications

(23 citation statements)

References 31 publications

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“…In the affected animal, hair follicles were more numerous, thinner and located higher in the dermis of the frontal skin; sebaceous and sweat glands were hypoplastic; teeth were absent with the exception of one malformed premolar on each side of the upper jaw; while horn development appeared normal. This animal died at 2 weeks of age of pulmonary infection, probably aggravated by the absence of ciliae and mucous glands in the respiratory tract, as usually observed in HED [6, 14].…”

Section: Discussionmentioning

confidence: 99%

“…Many mutations in EDA have already been described in humans and mice, which provide insights on the impact of the deletion that we report in this article. Karlskov et al [14] described a case of HED in cattle that was caused by a transcript variant containing a LINE1-derived pseudo exon between the first and the second exons of EDA . Since this pseudo exon results in a frameshift and a stop codon early in exon 2, we conclude that, in this HED case, the truncated protein encoded by only the first EDA exon would not be functional.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in EDAR , EDARADD and WNT10A are most frequently autosomal recessive, whereas mutations in EDA, which is located on the X chromosome, are inherited in a X-linked recessive pattern and cause the X-linked form of HED (XLHED) [14]. In contrast to males, females that are heterozygous for EDA mutations typically show less severe symptoms with a reduced degree of hypodontia, mosaic patterns of hypotrichosis, and defective sweat glands along Blaschko’s lines because of random X inactivation [15–17].…”

Section: Introductionmentioning

confidence: 99%

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Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia

et al. 2019

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Background In mammals, hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that is characterized by sparse hair, tooth abnormalities, and defects in cutaneous glands. Only four genes, EDA, EDAR, EDARADD and WNT10A account for more than 90% of HED cases, and EDA, on chromosome X, is involved in 50% of the cases. In this study, we explored an isolated case of a female Holstein calf with symptoms similar to HED. Results Clinical examination confirmed the diagnosis. The affected female showed homogeneous hypotrichosis and oligodontia as previously observed in bovine EDAR homozygous and EDA hemizygous mutants. Under light microscopy, the hair follicles were thinner and located higher in the dermis of the frontal skin in the affected animal than in the control. Moreover, the affected animal showed a five-fold increase in the number of hair follicles and a four-fold decrease in the diameter of the pilary canals. Pedigree analysis revealed that the coefficient of inbreeding of the affected calf (4.58%) was not higher than the average population inbreeding coefficient (4.59%). This animal had ten ancestors in its paternal and maternal lineages. By estimating the number of affected cases that would be expected if any of these common ancestors carried a recessive mutation, we concluded that, if they existed, other cases of HED should have been reported in France, which is not the case. Therefore, we assumed that the causal mutation was dominant and de novo. By analyzing whole-genome sequencing data, we identified a large chromosomal inversion with breakpoints located in the first introns of the EDA and XIST genes. Genotyping by PCR-electrophoresis the case and its parents allowed us to demonstrate the de novo origin of this inversion. Finally, using various sources of information we present a body of evidence that supports the hypothesis that this mutation is responsible for a skewed inactivation of X, and that only the normal X can be inactivated. Conclusions In this article, we report a unique case of X-linked HED affected Holstein female calf with an assumed full inactivation of the normal X-chromosome, thus leading to a severe phenotype similar to that of hemizygous males.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia

et al. 2019

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“…Two other examples from cattle with XLHED underscore some peculiarities of splicing defects in the EDA gene: in an affected calf carrying a single nucleotide variant located in the 5′-splice site of intron 8 (c.924+2G>T), not only the splicing of intron 8, but unexpectedly also the splicing of intron 7 was found to be altered ( Drögemüller et al 2002 ). In another XLHED affected calf, EDA transcripts were found to contain an extra 161 nucleotides, presumably derived by aberrant “exonization” of a LINE element inserted into intron 1 of the EDA gene ( Karlskov-Mortensen et al 2011 ). These examples show that genomic sequence changes in the EDA gene can result in unexpected splice defects and XLHED.…”

Section: Discussionmentioning

confidence: 99%

A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype

Waluk

Zur

Kaufmann

et al. 2016

G3 Genes|Genomes|Genetics

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X-linked hypohidrotic ectodermal dysplasia (XLHED) caused by variants in the EDA gene represents the most common ectodermal dysplasia in humans. We investigated three male mixed-breed dogs with an ectodermal dysplasia phenotype characterized by marked hypotrichosis and multifocal complete alopecia, almost complete absence of sweat and sebaceous glands, and altered dentition with missing and abnormally shaped teeth. Analysis of SNP chip genotypes and whole genome sequence data from the three affected dogs revealed that the affected dogs shared the same haplotype on a large segment of the X-chromosome, including the EDA gene. Unexpectedly, the whole genome sequence data did not reveal any nonsynonymous EDA variant in the affected dogs. We therefore performed an RNA-seq experiment on skin biopsies to search for changes in the transcriptome. This analysis revealed that the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. These dogs thus offer an excellent opportunity to gain insights into the complex splicing processes required for expression of the EDA gene, and other genes with large introns.

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“…Certain histological features in rats, such as mucous cell hyperplasia in chronic otitis media, show a closer resemblance to humans and underline the value of using diverse species models in otitis media research (Li et al, 2013). The finding of HED-associated otitis media in rats as well as mice suggests that dogs and cattle with HED (Hadji Rasouliha et al, 2018; Kowalczyk et al, 2011; Waluk et al, 2016; Karlskov-Mortensen et al, 2011; Seeliger et al, 2005) may also have otitis media. A better understanding of interspecies differences in HED-associated otitis media will increase the confidence in translating findings to human patients, in which the direct study of auditory-tube SMGs is difficult and where our current knowledge comes from histology of post-mortem samples (Orita et al, 2002; Berger, 1993).…”

Section: Discussionmentioning

confidence: 99%

Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia

Pozo

MacIntyre

Azar

et al. 2019

Disease Models &Amp; Mechanisms

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Patients with mutations in the ectodysplasin receptor signalling pathway genes – the X-linked ligand ectodysplasin-A ( EDA ), the receptor EDAR or the receptor adapter EDARADD – have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains Tabby ( Eda Ta ) and downless ( Edar dl-J/dl-J ) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in Eda Ta mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired ( swh ) rat strain carries a mutation in the Edaradd gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaradd swh/swh than those in unaffected heterozygous Edaradd swh/+ rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children.

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Exonization of a LINE1 fragment implicated in X-linked hypohidrotic ectodermal dysplasia in cattle

Cited by 16 publications

References 31 publications

Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia

Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia

A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype

Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia

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