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

Abstract

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.

A Nanopore Based Chromosome-Level Assembly Representing Atlantic Cod from the Celtic Sea

“…Localizing precise inversion breakpoints can be informative in functional studies as they may directly impact gene structure, such as has been reported in cattle ( Escouflaire et al 2019 ) or gene expression; by disrupting regulatory elements. Similarly, analyzing sequences close to a breakpoint may highlight signatures accompanying inversions such as the inverted repeat reported in Atlantic Herring ( Pettersson et al 2019 ) and provide insight into mechanisms by which inversions arise.…”

“…Localising precise inversion breakpoints can be informative in functional studies as they may directly impact gene structure, such as has been reported in cattle (Escouflaire et al 2019) or gene expression; by disrupting regulatory elements.…”

X-Linked Hypohidrotic Ectodermal Dysplasia in Crossbred Beef Cattle Due to a Large Deletion in EDA

“…The density of hair follicles in the affected calves presented in this study was only slightly greater than in unaffected calves. This is dissimilar to a calf with ECTD1, which had five times more hair follicles than a control calf [ 10 ]—this might be due to using different skin sites (scalp vs. flank) for follicular counts in the two variants of ECTD1. Sebaceous glands in the herein studied calves were morphologically normal.…”

“…HED has been documented in mice, dogs, cattle and rats [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Our understanding of EDA-related anhidrotic ectodermal dysplasia is based in large part on the Tabby ( Eda T a ) mouse [ 11 , 13 , 14 , 15 ].…”

“…The ability to ameliorate or abolish congenital defects of HED using short-term treatment with recombinant ectodysplasin was first demonstrated in Tabby mice and refined in a canine model, leading to successful treatment of human fetuses [ 16 , 17 , 18 , 19 ]. To date, there are eight reported pathogenic variants of the bovine EDA gene that, result in an ECTD1-like disease (OMIA 000543-9913) [ 8 , 9 , 10 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. They are potentially lethal since affected cattle are ill-thrifty due to oligodontia and the heightened risk for pneumonia and hypothermia [ 20 , 21 , 27 ].…”