title: In frame exon skipping in UBE3B is associated with developmental disorders and increased mortality in cattle.
abstract: BACKGROUND
  Inherited developmental diseases can cause severe animal welfare and economic problems in dairy cattle. The use of a small number of bulls for artificial insemination (AI) carries a risk that recessive defects rapidly enrich in the population. In recent years, an increasing number of Finnish Ayrshire calves have been identified with signs of ptosis, intellectual disability, retarded growth and mortality, which constitute an inherited disorder classified as PIRM syndrome.
  
  
  RESULTS
  We established a cohort of nine PIRM-affected calves and 38 unaffected half-siblings and performed a genome-wide association study (GWAS) to map the disease to a 700-kb region on bovine chromosome 17 (p = 1.55 × 10-9). Whole genome re-sequencing of an unaffected carrier, its affected progeny and 43 other unaffected animals from another breed identified a G > A substitution mutation at the last nucleotide of exon 23 in the ubiquitin protein ligase E3B encoding gene (UBE3B). UBE3B transcript analysis revealed in-frame exon skipping in the affected animals resulting in an altered protein lacking 40 amino acids, of which 20 are located in the conserved HECT-domain, the catalytic site of the UBE3B protein. Mutation screening in 129 Ayrshire AI bulls currently used in Finland indicated a high carrier frequency (17.1%). We also found that PIRM syndrome might be connected to the recently identified AH1 haplotype, which has a frequency of 26.1% in the United States Ayrshire population.
  
  
  CONCLUSIONS
  We describe PIRM syndrome in cattle, which is associated with the mutated UBE3B gene. The bovine phenotype resembles human Kaufman oculocerebrofacial syndrome, which is also caused by mutations in UBE3B. PIRM syndrome might be connected with the recently identified AH1 haplotype, which is associated with reduced fertility in the US Ayrshire population. This study enables the development of a genetic test to efficiently reduce the high frequency of mutant UBE3B in Ayrshires, significantly improving animal health and reducing economic loss.
authors.affiliation: Department of Production Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Paroninkuja 20, 04920 Saarentaus, Finland. heli.venhoranta@helsinki.fi.
authors.forename: Heli
authors.initials: H
authors.lastname: Venhoranta
authors.forename: Hubert
authors.initials: H
authors.lastname: Pausch
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Flisikowski
authors.forename: Christine
authors.initials: C
authors.lastname: Wurmser
authors.forename: Juhani
authors.initials: J
authors.lastname: Taponen
authors.forename: Helena
authors.initials: H
authors.lastname: Rautala
authors.forename: Alexander
authors.initials: A
authors.lastname: Kind
authors.forename: Angelika
authors.initials: A
authors.lastname: Schnieke
authors.forename: Ruedi
authors.initials: R
authors.lastname: Fries
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
authors.forename: Magnus
authors.initials: M
authors.lastname: Andersson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002874:Chromosome Mapping; D005091:Exons; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D019066:Facies; D055106:Genome-Wide Association Study; D006239:Haplotypes; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D008969:Molecular Sequence Data; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D044767:Ubiquitin-Protein Ligases