Categories: Mortality / aging (incl. embryonic lethal)

Possibly relevant human trait(s) and/or gene(s) (MIM number): 602233 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific name: Haplotype HH1

Species-specific symbol: HH1

History: Using genotype data from tens of thousands of North American Holsteins, Jerseys and Brown Swiss cattle each genotyped with approximately 50K SNPs on the BovineSNP50 BeadChip, VanRaden et al. (2011) identified five new recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. Three of these haplotypes occur in Holsteins only, and (following a convention proposed by breed-association staff) VanRaden et al. (2011) named them HH1, HH2 and HH3, where the first H stands for Holstein and the second H for haplotype. The disorder described in this OMIA entry is HH1, which maps to chromosome BTA5, at 58-66Mb (UMD 3.0 genome assembly). Fritz et al. (2013) confirmed the existence and location of HH1.

Molecular basis: Adams et al. (2012) revealed the causal mutation of HH1 as "a nonsense mutation in APAF1 . . . , which is predicted to truncate approximately one-third of the encoded APAF1 protein". Because functional APAF1 peptide is required for embryo development, homozygosity for this allele results in natural spontaneous abortion, and, consequently, perceived reduced fertility in carrier bulls that happen to be mated to carrier cows.

Adams et al. (2016) published the causal mutation as being "a nonsense mutation in APAF1 (apoptotic protease activating factor 1; APAF1 p.Q579X) within HH1 using whole-genome resequencing of Chief and 3 of his sons. This mutation is predicted to truncate 670 AA (53.7%) of the encoded APAF1 protein that contains a WD40 domain critical to protein–protein interactions."

Clinical features: Park et al. (2023) report a Holstein foetus with schistosomus reflexus that tested homozygous for the APAF1 variant identified by Adams et al. (2012) (OMIAvariantID:286).

Prevalence: Adams et al. (2016) :"Subsequent commercial genotyping of 246,773 Holsteins revealed 5,299 APAF1 heterozygotes and zero homozygotes for the mutation. . . . This mutation has caused an estimated 525,000 spontaneous abortions worldwide over the past 35 years, accounting for approximately $420 million in losses."

Breeds: Blanco Orejinegro, Colombia (Cattle) (VBO_0004602), Holstein (black and white) (Cattle) (VBO_0000237).

Associated gene: