A nonsense mutation in B3GALNT2 is concordant with hydrocephalus in Friesian horses

• Published in: BMC genomics Vol. 16; no. 1; p. 761
• Main Authors: Ducro, Bart J, Schurink, Anouk, Bastiaansen, John W M, Boegheim, Iris J M, van Steenbeek, Frank G, Vos-Loohuis, Manon, Nijman, Isaac J, Monroe, Glen R, Hellinga, Ids, Dibbits, Bert W, Back, Willem, Leegwater, Peter A J
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09-10-2015; BioMed Central
• Subjects: Alleles; Analysis; Animal Breeding and Genetics; Animal Breeding and Genomics; Animals; Breeding; Codon, Nonsense - genetics; DNA sequencing; Exons; Female; Fokkerij en Genetica; Fokkerij en Genomica; Genetic aspects; Genome-Wide Association Study; Horse Diseases - genetics; Horses; Humans; Hydrocephalus - genetics; Hydrocephalus - pathology; Inbreeding; Leerstoelgroep Fokkerij en genetica; N-Acetylgalactosaminyltransferases - genetics; Nucleotide sequencing; Polymorphism, Single Nucleotide; Pregnancy; WIAS
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-015-1936-z

Hydrocephalus in Friesian horses is a developmental disorder that often results in stillbirth of affected foals and dystocia in dams. The occurrence is probably related to a founder effect and inbreeding in the population. The aim of our study was to find genomic associations, to investigate the mode of inheritance, to allow a DNA test for hydrocephalus in Friesian horses to be developed. In case of a monogenic inheritance we aimed to identify the causal mutation.
A genome-wide association study of hydrocephalus in 13 cases and 69 controls using 29,720 SNPs indicated the involvement of a region on ECA1 (P <1.68 × 10(-6)). Next generation DNA sequence analysis of 4 cases and 6 controls of gene exons within the region revealed a mutation in β-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2) as the likely cause of hydrocephalus in Friesian horses. The nonsense mutation XM_001491545 c.1423C>T corresponding to XP_001491595 p.Gln475* was identical to a B3GALNT2 mutation identified in a human case of muscular dystrophy-dystroglycanopathy with hydrocephalus. All 16 available cases and none of the controls were homozygous for the mutation, and all 17 obligate carriers (= dams of cases) were heterozygous. A random sample of the Friesian horse population (n = 865) was tested for the mutation in a commercial laboratory. One-hundred and forty-seven horses were carrier and 718 horses were homozygous for the normal allele; the estimated allele frequency in the Friesian horse population is 0.085.
Hydrocephalus in Friesian horses has an autosomal recessive mode of inheritance. A nonsense mutation XM_001491545 c.1423C>T corresponding to XP_001491595 p.Gln475* in B3GALNT2 (1:75,859,296-75,909,376) is concordant with hydrocephalus in Friesian horses. Application of a DNA test in the breeding programme will reduce the losses caused by hydrocephalus in the Friesian horse population.