title: Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle.
abstract: BACKGROUND
  Bovine progressive degenerative myeloencephalopathy (Weaver syndrome) is a neurodegenerative disorder in Brown Swiss cattle that is characterized by progressive hind leg weakness and ataxia, while sensorium and spinal reflexes remain unaffected. Although the causal mutation has not been identified yet, an indirect genetic test based on six microsatellite markers and consequent exclusion of Weaver carriers from breeding have led to the complete absence of new cases for over two decades. Evaluation of disease status by imputation of 41 diagnostic single nucleotide polymorphisms (SNPs) and a common haplotype published in 2013 identified several suspected carriers in the current breeding population, which suggests a higher frequency of the Weaver allele than anticipated. In order to prevent the reemergence of the disease, this study aimed at mapping the gene that underlies Weaver syndrome and thus at providing the basis for direct genetic testing and monitoring of today's Braunvieh/Brown Swiss herds.
  
  
  RESULTS
  Combined linkage/linkage disequilibrium mapping on Bos taurus chromosome (BTA) 4 based on Illumina Bovine SNP50 genotypes of 43 Weaver-affected, 31 Weaver carrier and 86 Weaver-free animals resulted in a maximum likelihood ratio test statistic value at position 49,812,384 bp. The confidence interval (0.853 Mb) determined by the 2-LOD drop-off method was contained within a 1.72-Mb segment of extended homozygosity. Exploitation of whole-genome sequence data from two official Weaver carriers and 1145 other bulls that were sequenced in Run4 of the 1000 bull genomes project showed that only a non-synonymous SNP (rs800397662) within the PNPLA8 gene at position 49,878,773 bp was concordant with the Weaver carrier status. Targeted SNP genotyping confirmed this SNP as a candidate causal mutation for Weaver syndrome. Genotyping for the candidate causal mutation in a random sample of 2334 current Braunvieh animals suggested a frequency of the Weaver allele of 0.26 %.
  
  
  CONCLUSIONS
  Through combined use of exhaustive sequencing data and SNP genotyping results, we were able to provide evidence that supports the non-synonymous mutation at position 49,878,773 bp as the most likely causal mutation for Weaver syndrome. Further studies are needed to uncover the exact mechanisms that underlie this syndrome.
authors.affiliation: Chair of Animal Genetics and Husbandry, Ludwig-Maximilians-Universitaet Muenchen, Veterinaerstr. 13, 80539, Munich, Germany.|Tierzuchtforschung e.V. Muenchen, Senator-Gerauer-Str. 23, 85586, Poing, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kunz
authors.affiliation: Chair of Animal Genetics and Husbandry, Ludwig-Maximilians-Universitaet Muenchen, Veterinaerstr. 13, 80539, Munich, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rothammer
authors.affiliation: Chair of Animal Breeding, Technische Universitaet Muenchen, Liesel-Beckmann-Straße (Hochfeldweg) 1, 85354, Freising-Weihenstephan, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Pausch
authors.affiliation: ZuchtData EDV-Dienstleistungen GmbH, Dresdner Straße 89/19, 1200, Vienna, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Schwarzenbacher
authors.affiliation: Qualitas AG, Chamerstr. 56, 6300, Zug, Switzerland.
authors.forename: Franz R
authors.initials: FR
authors.lastname: Seefried
authors.affiliation: Institute of Veterinary Pathology, Ludwig-Maximilians-Universitaet Muenchen, Veterinaerstr. 13, 80539, Munich, Germany.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Matiasek
authors.affiliation: Tierzuchtforschung e.V. Muenchen, Senator-Gerauer-Str. 23, 85586, Poing, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Seichter
authors.affiliation: Tierzuchtforschung e.V. Muenchen, Senator-Gerauer-Str. 23, 85586, Poing, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Russ
authors.affiliation: Chair of Animal Breeding, Technische Universitaet Muenchen, Liesel-Beckmann-Straße (Hochfeldweg) 1, 85354, Freising-Weihenstephan, Germany.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Fries
authors.affiliation: Chair of Animal Genetics and Husbandry, Ludwig-Maximilians-Universitaet Muenchen, Veterinaerstr. 13, 80539, Munich, Germany. ivica.medjugorac@gen.vetmed.uni-muenchen.de.
authors.forename: Ivica
authors.initials: I
authors.lastname: Medugorac
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000662:veterinary*; D001483:Base Sequence; D001947:Breeding; D002417:Cattle / Q000235:genetics; D002418:Cattle Diseases / Q000235:genetics*; D002874:Chromosome Mapping / Q000662:veterinary; D004679:Encephalomyelitis / Q000235:genetics / Q000662:veterinary*; D023281:Genomics / Q000379:methods; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D016013:Likelihood Functions; D015810:Linkage Disequilibrium; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide