Clinicopathological and Genomic Characterization of a Simmental Calf with Generalized Bovine Juvenile Angiomatosis

Bovine juvenile angiomatosis (BJA) comprises a group of single or multiple proliferative vascular anomalies in the skin and viscera of affected calves. The purpose of this study was to characterize the clinicopathological phenotype of a 1.5-month-old Simmental calf with multiple cutaneous, subcutaneous, and visceral vascular hamartomas, which were compatible with a generalized form of BJA, and to identify genetic cause for this phenotype by whole-genome sequencing (WGS). The calf was referred to the clinics as a result of its failure to thrive and the presence of multiple cutaneous and subcutaneous nodules, some of which bled abundantly following spontaneous rupture. Gross pathology revealed similar lesions at the inner thoracic wall, diaphragm, mediastinum, pericardium, inner abdominal wall, and mesentery. Histologically, variably sized cavities lined by a single layer of plump cells and supported by a loose stroma with occasional acute hemorrhage were observed. Determined by immunochemistry, the plump cells lining the cavities displayed a strong cytoplasmic signal for PECAM-1, von Willebrand factor, and vimentin. WGS revealed six private protein-changing variants affecting different genes present in the calf and absent in more than 4500 control genomes. Assuming a spontaneous de novo mutation event, one of the identified variants found in the PREX1, UBE3B, PCDHGA2, and ZSWIM6 genes may represent a possible candidate pathogenic variant for this rare form of vascular malformation

CATTLE CONGENITAL PSEUDOMYOTONIA: AN ANIMAL MODEL FOR INVESTIGATING HUMAN BRODY DISEASE

An inherited muscle disorder defined as \u201ccongenital pseudomyotonia\u201d has been described in two important Italian cattle breeds and, as a single case, in a cross-breed calf in the Netherlands. Clinically the disorder is characterized by an exercise-induced muscle contraction. Cattle pseudomyotonia has been well characterized at both genetic and biochemical levels. By DNA sequencing of affected calves, we have provided evidence of mutations in ATP2A1 gene coding for sarco(endo)plasmic reticulum Ca2+-ATPase, isoform1 (SERCA1). Moreover we have demonstrated that cattle pathological muscles are characterized by a selective reduction in the level of expression of SERCA1. On the basis of symptoms and of genetic and biochemical confirmations, cattle pseudomyotonia has been defined as the true counterpart of human Brody disease, a rare inherited disorder of skeletal muscle due to a SERCA1 deficiency, resulting from a defect of ATP2A1 gene. Although for both Brody disease and pseudomyotonia the selective reduction in the expression levels of SERCA1, has been indicated as causative of the disease, the pathophysiological mechanism underlying this deficiency has not yet been clarified. Recently, we have presented the crystal structure of bovine SERCA1. This result together with data on the possible role of the Quality Control System, ubiquitin-proteasome, in the reduction of expression levels of the mutated SERCA1, demonstrate that a single mutation is sufficient to perturb the three dimensional structure of SERCA1 protein and induce a genetic disease. This study reflects the enormous potential of domestic animals to gain further insights into human medicine

A missense mutation in the skeletal muscle chloride channel 1 (CLCN1) as candidate causal mutation for congenital myotonia in a New Forest pony

A 7-month-old New Forest foal presented for episodes of recumbency and stiffness with myotonic discharges on electromyography. The observed phenotype resembled congenital myotonia caused by CLCN1 mutations in goats and humans. Mutation of the CLCN1 gene was considered as possible cause and mutation analysis was performed. The affected foal was homozygous for a missense mutation (c.1775A>C, p.D592A) located in a well conserved domain of the CLCN1 gene. The mutation showed a recessive mode of inheritance within the reported pony family. Therefore, this CLCN1 polymorphism is considered to be a possible cause of congenital myotonia