Dysfunctional <i>CRPPA</i> is responsible for recessively inherited Hereford hydrocephalus with muscular dystrophy and retinal dysplasia

Hydrocephalus was first reported in Hereford cattle over 65 years ago; although no cause was identified in prior reports, it was suspected to be genetic. Advancements in reproductive technology and genomics have allowed for a determinative investigation of recent cases. Clinical and genomic data from 2 natural cases were followed by in vitro mating of a mother-son pair, each of which previously produced affected calves. Embryo transfer resulted in 7 calves, one of which had hydrocephalus, retinal dysplasia, and muscular dystrophy. Whole-genome sequencing of 2 affected calves, their sire, dams, and one related individual was supplemented with data from additional Hereford/Hereford cross cattle. Analyses identified a splice site variant in <i>CRPPA</i> (CDP-L-ribitol pyrophosphorylase A or <i>ISPD</i>) for which the affected calves were homozygous. This variant was not found in the homozygous state in any other individuals genotyped, in sequence data provided by the breed association, or in a public database query. The splice site mutation resulted in retention of intron 7, encompassing a stop codon predicted to truncate the protein. The transcript was expressed in the affected calf and the protein was detected in several tissues. Although translated into protein, immunohistochemistry demonstrated a lack of normal glycosylation of α-dystroglycan in the affected calf, which is necessary for a variety of processes including sarcolemma stability and neuronal migration. This phenotype is like Walker-Warburg syndrome in humans, some cases of which are attributed to mutations in <i>CRPPA</i>. This advancement allows for testing to eliminate carriers and potential for affected calves.