Categories: Behaviour / neurological phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 244450 (trait) , 608047 (gene)

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.

Genetic engineering: Unknown
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).

Breed: 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

Associated gene: