Abstract
BackgroundInherited 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.ResultsWe 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-890) contains supplementary material, which is available to authorized users.
Highlights
Inherited developmental diseases can cause severe animal welfare and economic problems in dairy cattle
We report that PIRM syndrome in cattle is associated with an exon skipping mutation in ubiquitin protein ligase E3B (UBE3B) and this mutation is present at high frequency in the sample of artificial insemination (AI) bulls tested
The phenotype has been defined as PIRM syndrome according to its typical features
Summary
Inherited developmental diseases can cause severe animal welfare and economic problems in dairy cattle. 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. Inherited developmental diseases can cause severe animal welfare and economic problems in dairy cattle breeding. In the past few years, an increasing number of Finnish Ayrshire calves have been identified with a combination of severe symptoms including ptosis, intellectual disability, retarded growth and mortality, a disorder classified as PIRM syndrome. Bovine PIRM resembles the human autosomal recessive neurodevelopmental disorder Kaufman oculocerebrofacial syndrome, known as blepharophimosis-ptosis-intellectual disability syndrome (MIM 615057, MIM 244450), caused by ubiquitin protein ligase E3B (UBE3B) mutations [4,5,6]. The best known example of these defects is Angelman syndrome characterised by intellectual disability, absence of speech, motor dysfunction and seizures (MIM 105830) caused by loss of function of the imprinted gene UBE3A (ubiquitin protein ligase E3A) [10,11]
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