A missense mutation in the highly conserved TNF-like domain of Ectodysplasin A is the candidate causative variant for X-linked hypohidrotic ectodermal dysplasia in Limousin cattle: Clinical, histological, and molecular analyses.

Ectodysplasin A related hypohidrotic ectodermal dysplasia (XLHED) is a well-studied fetal developmental disorder in mammals that mainly affects ectodermal structures. It has been identified in a variety of species, including mice, rats, dogs, cattle, and humans. Here, we report the clinical, histological, and molecular biological analyses of a case of XLHED in Limousin cattle. An affected Limousin calf showed pathognomonic signs of ectodermal dysplasia, i.e. sparse hair and characteristic dental aplasia. Histopathologic comparison of hairy and glabrous skin and computed tomography of the mandible confirmed the phenotypic diagnosis. In addition, a keratoconjunctivitis sicca was noted in one eye, which was also confirmed histopathologically. To identify the causative variant, we resequenced the bovine X-chromosomal ectodysplasin A gene (EDA) of the affected calf and compared the sequences to the bovine reference genome. A single missense variant (rs439722471) at position X:g.80411716T>C (ARS-UCD1.3) was identified. The variant resulted in an amino acid substitution from glutamic acid to glycine within the highly conserved TNF-like domain. To rule out the possibility that the variant was relatively common in the cattle population we genotyped 2,016 individuals including 40% Limousin cattle by fluorescence resonance energy transfer analysis. We also tested 5,116 multibreed samples from Run9 of the 1000 Bull Genomes Project for the said variant. The variant was not detected in any of the cattle tested, confirming the assumption that it was the causative variant. This is the first report of Ectodysplasin A related hypohidrotic ectodermal dysplasia in Limousin cattle and the description of a novel causal variant in cattle.

Frameshift Variant in Novel Adenosine-A1-Receptor Homolog Associated With Bovine Spastic Syndrome/Late-Onset Bovine Spastic Paresis in Holstein Sires.

Since their first description almost 100 years ago, bovine spastic paresis (BSP) and bovine spastic syndrome (BSS) are assumed to be inherited neuronal-progressive diseases in cattle. Affected animals are characterized by (frequent) spasms primarily located in the hind limbs, accompanied by severe pain symptoms and reduced vigor, thus initiating premature slaughter or euthanasia. Due to the late onset of BSP and BSS and the massively decreased lifespan of modern cattle, the importance of these diseases is underestimated. In the present study, BSP/BSS-affected German Holstein breeding sires from artificial insemination centers were collected and pedigree analysis, genome-wide association studies, whole genome resequencing, protein-protein interaction network analysis, and protein-homology modeling were performed to elucidate the genetic background. The analysis of 46 affected and 213 control cattle revealed four significantly associated positions on chromosome 15 (BTA15), i.e., AC_000172.1:g.83465449A>G (-log10P = 19.17), AC_000172.1:g.81871849C>T (-log10P = 8.31), AC_000172.1:g.81872621A>T (-log10P = 6.81), and AC_000172.1:g.81872661G>C (-log10P = 6.42). Two additional loci were significantly associated located on BTA8 and BTA19, i.e., AC_000165.1:g.71177788T>C and AC_000176.1:g.30140977T>G, respectively. Whole genome resequencing of five affected individuals and six unaffected relatives (two fathers, two mothers, a half sibling, and a full sibling) belonging to three different not directly related families was performed. After filtering, a homozygous loss of function variant was identified in the affected cattle, causing a frameshift in the so far unknown gene locus LOC100848076 encoding an adenosine-A1-receptor homolog. An allele frequency of the variant of 0.74 was determined in 3,093 samples of the 1000 Bull Genomes Project.