title: A nonsense mutation in B3GALNT2 is concordant with hydrocephalus in Friesian horses.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Animal Breeding and Genomics Centre, Wageningen University, PO Box 338, 6700 AH, Wageningen, The Netherlands. bart.ducro@wur.nl.
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Ducro
authors.affiliation: Animal Breeding and Genomics Centre, Wageningen University, PO Box 338, 6700 AH, Wageningen, The Netherlands. anouk3.schurink@wur.nl.
authors.forename: Anouk
authors.initials: A
authors.lastname: Schurink
authors.affiliation: Animal Breeding and Genomics Centre, Wageningen University, PO Box 338, 6700 AH, Wageningen, The Netherlands. john.bastiaansen@wur.nl.
authors.forename: John W M
authors.initials: JW
authors.lastname: Bastiaansen
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, PO Box 80154, 3508 TD, Utrecht, The Netherlands. i.j.m.boegheim@students.uu.nl.
authors.forename: Iris J M
authors.initials: IJ
authors.lastname: Boegheim
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, PO Box 80154, 3508 TD, Utrecht, The Netherlands. f.g.vansteenbeek@uu.nl.
authors.forename: Frank G
authors.initials: FG
authors.lastname: van Steenbeek
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, PO Box 80154, 3508 TD, Utrecht, The Netherlands. m.vos@uu.nl.
authors.forename: Manon
authors.initials: M
authors.lastname: Vos-Loohuis
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, The Netherlands. inijman@umcutrecht.nl.
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, The Netherlands. g.monroe@umcutrecht.nl.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Monroe
authors.affiliation: Koninklijke Vereniging "Het Friesch Paarden-Stamboek", PO Box 624, 9200 AP, Drachten, The Netherlands. idshellinga@kfps.nl.
authors.forename: Ids
authors.initials: I
authors.lastname: Hellinga
authors.affiliation: Animal Breeding and Genomics Centre, Wageningen University, PO Box 338, 6700 AH, Wageningen, The Netherlands. bert.dibbits@wur.nl.
authors.forename: Bert W
authors.initials: BW
authors.lastname: Dibbits
authors.affiliation: Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112-114, 3584 CM, Utrecht, The Netherlands. W.Back@uu.nl.|Department of Surgery and Anaesthesiology of Domestic Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820, Merelbeke, Belgium. W.Back@uu.nl.
authors.forename: Willem
authors.initials: W
authors.lastname: Back
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, PO Box 80154, 3508 TD, Utrecht, The Netherlands. P.A.J.Leegwater@uu.nl.
authors.forename: Peter A J
authors.initials: PA
authors.lastname: Leegwater
mesh_terms: D000483:Alleles; D000818:Animals; D001947:Breeding; D018389:Codon, Nonsense / Q000235:genetics*; D005091:Exons; D005260:Female; D055106:Genome-Wide Association Study; D006734:Horse Diseases / Q000235:genetics*; D006736:Horses; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics* / Q000473:pathology; D007178:Inbreeding; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy
chemical_list: D018389:Codon, Nonsense; D017350:N-Acetylgalactosaminyltransferases