Genetic background of dwarfism and hydrocephalus in Friesian horses

Abstract

Background: The Friesian horse breed suffered several population bottlenecks and has a high inbreeding coefficient. This has resulted in a number of genetic disorders. Two of these disorders are dwarfism and hydrocephalus. Dwarfism is characterized by reduction of long bone growth and disproportionate dwarfism, with joint laxity and ribcage abnormalities. Hydrocephalus in the Friesian horse is characterized by severe distension of the cranium and is likely caused by stenosis of the jugular foramen. Dwarfism and hydrocephalus are suspected to be caused by autosomal, recessive, monogenetic mutations. The aim of this study is to identify the mutations responsible for dwarfism and hydrocephalus in the Friesian horse. Results: Hydrocephalus is associated with a region on ECA1. All 13 cases displayed homozygosity from 74.9 to 75.5 Mb (0.58 Mb in length) in accordance with recessive inheritance from a single founder. All 16 available cases are homozygous for a mutation that introduces a stop codon in B3GALNT2, coding for β-1,3-N-acetylgalactosaminyltransferase 2. Exactly the same mutation has been found in a human case of muscular dystrophy with hydrocephalus. None of the 68 controls were homozygous for this mutation. The B3GALNT2 encoded protein is one of many modifiers of extracellular matrix polysaccharides. Dwarfism, on the other hand, is associated with a region on ECA14. All four cases were homozygous for a missense mutation in B4GALT7, encoding xylosylprotein β-1,4-galactosyltransferase 7. The arginine amino acid is highly conserved, and the mutation is not a functional mutation but rather a splicing restricting mutation. All 29 available cases were homozygous for the mutation, eight obligate carriers were heterozygous and none of the 177 control horses were homozygous for the mutation. Both B3GALNT2 and B4GALT7 are involved in glycosylation and are therefore important factors of the extracellular matrix. Conclusions: a nonsense mutation in B3GALNT2 and a missense mutation in B4GALT7 are concordant with hydrocephalus and dwarfism respectively. Knowledge of the causative mutation can eradicate both diseases by selective breeding and might help select candidate genes for other genetic diseases in the breed.