OMIA:001934-9913 : Ptosis, intellectual disability, retarded growth and mortality (PIRM) syndrome (Haplotype AH1) in Bos taurus (taurine cattle)
Categories: Behaviour / neurological phene
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2014
Species-specific name: Haplotype AH1
Species-specific symbol: AH1
History: This syndrome was first described by Venhoranta et al. (2014), who also reported its causal mutation.
Mapping: By conducting a GWAS on 9 affected and 37 normal half-sibs, each genotyped with the Illumina BovineHD Bead chip (yielding 623,881 informative SNPs), Venhoranta et al. (2014) mapped this disorder to a region between 65,659,074 bp and 65,981,740 bp (UMD3.1 assembly) on chromosome BTA17. Subsequent homozygosity mapping reduced the candidate region to 713 kb (65,645,831 bp - 66,358,629 bp), which contains 14 genes.
Using a strategy similar to that of VanRaden et al. (2011), Cooper et al. (2014) discovered a "haplotype [which they named AH1] that affects Aryshire fertility . . . on Bos Taurus chromosome 17 in the range 65.9 to 66.2".
Molecular basis: Comparison of sequence of the 713kb candidate region (mentioned in the mapping section above) in an obligate carrier, one of its offspring, 43 members of the Fleckvieh breed (in which the disorder has never been reported) and 191 non-Fleckviehs from the 1000-bulls project revealed 2 candidate causal SNVs: a coding variant and an intronic variant of the gene UBE3B, which encodes ubiquitin protein ligase E3B, and mutations in which cause a similar syndrome in humans (see MIM links above). Sequencing of animals in other families in which the disorder segregates pointed to the coding variant (rs475678587G>A; p.E692E; Chr17:65,921,497 bp) as being causal. This synonymous variant occurs at the very last nucleotide of exon 23, at the junction with intron 23, resulting in skipping of the entire exon 23. As reported by Venhoranta et al. (2014), this results "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."
In their table of reduced-fertility haplotypes, Cole et al. (2014) list this UBE3B mutation as being causal for the infertility effect of haplotyoe AH1.
Have human generated variants been created, e.g. through genetic engineering and gene editing
Prevalence: As reported by Venhoranta et al. (2014), "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."
Null et al. (2017) reported the frequency of AH1 in US Ayrshires to be 22.2%.
Guarini et al. (2019) reported the frequency of the AH1 haplotype in Canadian Ayrshires was less than 1% from 1997 to 2008 after which it rose to be around 10.3% in 2014 (estimated from their Figure 2).
Ayrshire, Finland (Cattle) (VBO_0002298).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|UBE3B||ubiquitin protein ligase E3B||Bos taurus||17||NC_037344.1 (63696686..63650234)||UBE3B||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|404||Ayrshire, Finland (Cattle)||Ptosis, intellectual disability, retarded growth and mortality (PIRM) syndrome||UBE3B||splicing||Naturally occurring variant||ARS-UCD1.2||17||g.63668380C>T||c.2076G>A||p.(E692E)||ENSBTAT00000003493.5:c.2076G>A ENSBTAP00000003493.4:p.Glu692=||rs475678587||rs475678587||2014||25306138||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Variant rsID kindly provided or confirmed by Hubert Pausch, including information from Additional Table 6 of Jansen et al. (2013) BMC Genomics201314:446 https://doi.org/10.1186/1471-2164-14-446|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2023||Ask-Gullstrand, P., Strandberg, E., Båge, R., Rius-Vilarrasa, E., Berglund, B. :|
|The effect of genetic defects on pregnancy loss in Swedish dairy cattle. J Dairy Sci , 2023. Pubmed reference: 37977438. DOI: 10.3168/jds.2023-24159.|
|2019||Guarini, A.R., Sargolzaei, M., Brito, L.F., Kroezen, V., Lourenco, D.A.L., Baes, C.F., Miglior, F., Cole, J.B., Schenkel, F.S., Guarini, A.R., Sargolzaei, M., Brito, L.F., Kroezen, V., Lourenco, D.A.L., Baes, C.F., Miglior, F., Cole, J.B., Schenkel, F.S. :|
|Estimating the effect of the deleterious recessive haplotypes AH1 and AH2 on reproduction performance of Ayrshire cattle. J Dairy Sci 102:5315-5322, 2019. Pubmed reference: 30954262. DOI: 10.3168/jds.2018-15366.|
|2017||Null, D.J., Hutchison, J.L., Bickhart, D.M., VanRaden, P.M., Cole, J.B. :|
|Discovery of a haplotype affecting fertility in Ayrshire dairy cattle and identification of a putative causal variant. J. Dairy Sci. 100 (Suppl. 2):199 (Abstract 206), 2017.|
|2016||Cole, J.B., Null, D.J., VanRaden, P.M. :|
|Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility. J Dairy Sci 99:7274-88, 2016. Pubmed reference: 27394947. DOI: 10.3168/jds.2015-10777.|
|2014||Cole, J.B., VanRaden, P.M., Null, D.J., Hutchison, J.L., Cooper, T.A., Hubbard, S.M. :|
|Haplotype tests for recessive disorders that affect fertility and other traits. AIP RESEARCH REPORT GENOMIC3 (09-13); http://aipl.arsusda.gov/reference/recessive_haplotypes_ARR-G3.html , 2014.|
|Cooper, T.A., Wiggans, G.R., Null, D.J., Hutchison, J.L., Cole, J.B. :|
|Genomic evaluation, breed identification, and discovery of a haplotype affecting fertility for Ayrshire dairy cattle. J Dairy Sci 97:3878-82, 2014. Pubmed reference: 24679938. DOI: 10.3168/jds.2013-7427.|
|Venhoranta, H., Pausch, H., Flisikowski, K., Wurmser, C., Taponen, J., Rautala, H., Kind, A., Schnieke, A., Fries, R., Lohi, H., Andersson, M. :|
|In frame exon skipping in UBE3B is associated with developmental disorders and increased mortality in cattle. BMC Genomics 15:890, 2014. Pubmed reference: 25306138. DOI: 10.1186/1471-2164-15-890.|
|2011||VanRaden, P.M., Olson, K.M., Null, D.J., Hutchison, J.L. :|
|Harmful recessive effects on fertility detected by absence of homozygous haplotypes. J Dairy Sci 94:6153-61, 2011. Pubmed reference: 22118103. DOI: 10.3168/jds.2011-4624.|
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