OMIA 001934-9913 : Ptosis, intellectual disability, retarded growth and mortality (PIRM) syndrome (Haplotype AH1) in Bos taurus

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 244450 , 244450

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.

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).

Breed: Finnish Ayrshire.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
UBE3B ubiquitin protein ligase E3B Bos taurus 17 NC_037344.1 (63696708..63650234) UBE3B Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Finnish Ayrshire Ptosis, intellectual disability, retarded growth and mortality (PIRM) syndrome UBE3B splicing UMD3.1.1 17 g.65921497G>A p.E692E 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

References


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.
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. :
Estimating the effect of the deleterious recessive haplotypes AH1 and AH2 on reproduction performance of Ayrshire cattle. J Dairy Sci :, 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.

Edit History


  • Created by Frank Nicholas on 25 Oct 2014
  • Changed by Frank Nicholas on 25 Oct 2014
  • Changed by Frank Nicholas on 31 Oct 2014
  • Changed by Frank Nicholas on 24 Mar 2015
  • Changed by Frank Nicholas on 11 Apr 2019