OMIA:000001-9913 : Haplotype with homozygous deficiency HH1, APAF1-related in Bos taurus (taurine cattle)
In other species: indicine cattle (zebu)
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."
Have human generated variants been created, e.g. through genetic engineering and gene editing
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."
Blanco Orejinegro, Colombia (Cattle) (VBO_0004602),
Holstein (black and white) (Cattle) (VBO_0000237).
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|
|APAF1||apoptotic peptidase activating factor 1||Bos taurus||5||NC_037332.1 (62782018..62871543)||APAF1||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|
|286||Blanco Orejinegro, Colombia (Cattle) Holstein (black and white) (Cattle)||Abortion due to a nonsense mutation in APAF1 on haplotype HH1||APAF1||nonsense (stop-gain)||Naturally occurring variant||ARS-UCD1.2||5||g.62810245C>T||c.1741C>T||p.(Q581*)||Variant initially reported in Holstein Friesian cattle and later reported in additional breeds: PMID:34779908.||rs448942533||rs448942533||2016||27289157||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Breed information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (https://www.icbf.com/wp/?page_id=2170)|
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.|
|Bengtsson, C., Stålhammar, H., Thomasen, J.R., Fikse, W.F., Strandberg, E., Eriksson, S. :|
|Mating allocations in Holstein combining genomic information and linear programming optimization at the herd level. J Dairy Sci , 2023. Pubmed reference: 37028963. DOI: 10.3168/jds.2022-22926.|
|Park, W., Chai, H.H., Lim, D., Dang, C., Lee, J., Kim, J., Jeong, H., Lee, T., Lee, K.C., Lee, K. :|
|Case report: Investigation of genetic mutations in a case of schistosomus reflexus in a Holstein dairy cattle fetus in Korea. Front Vet Sci 10:1238544, 2023. Pubmed reference: 37671278. DOI: 10.3389/fvets.2023.1238544.|
|Sudhakar, A., Nayee, N., Saha, S., Donthula, S.K., Poojara, H.V., Gohil, T., Patel, A.C., Maurya, B.K. :|
|Role of genetic introgression in introducing mutant alleles in Bos indicus cattle and prevalence of lethal genetic disorders in Bos taurus × Bos indicus and Bos indicus cattle in India. Trop Anim Health Prod 55:399, 2023. Pubmed reference: 37940810. DOI: 10.1007/s11250-023-03798-8.|
|2022||Albertino, L.G., Albuquerque, A.L.H., Ferreira, J.F., Oliveira, J.P.M., Borges, A.S., Patelli, T.H.C., Oliveira-Filho, J.P. :|
|Allele frequency of APAF1 mutation in Holstein cattle in Brazil. Front Vet Sci 9:822224, 2022. Pubmed reference: 35280144. DOI: 10.3389/fvets.2022.822224.|
|2021||Caivio-Nasner, S., López-Herrera, A., González-Herrera, L.G., Rincón, J.C. :|
|Frequency of genotypic markers for genetic disorders, colour, polledness, and major genes in Blanco Orejinegro cattle. Trop Anim Health Prod 53:546, 2021. Pubmed reference: 34779908. DOI: 10.1007/s11250-021-02990-y.|
|2020||Kamiński, S. :|
|Novel method for identification of the lethal mutation in bovine APAF1 gene and its preliminary prevalence in Polish Holstein-Friesian bulls. Pol J Vet Sci 23:157-160, 2020. Pubmed reference: 32233301. DOI: 10.24425/pjvs.2020.132760.|
|2018||Ghanem, M.E., Nishibori, M., Isobe, N., Hisaeda, K. :|
|Detection of APAF1 mutation in Holstein cows and mummified foetuses in Japanese dairy herds. Reprod Domest Anim 53:137-142, 2018. Pubmed reference: 29076565. DOI: 10.1111/rda.13081.|
|2016||Adams, H.A., Sonstegard, T.S., VanRaden, P.M., Null, D.J., Van Tassell, C.P., Larkin, D.M., Lewin, H.A. :|
|Identification of a nonsense mutation in APAF1 that is likely causal for a decrease in reproductive efficiency in Holstein dairy cattle. J Dairy Sci 99:6693-701, 2016. Pubmed reference: 27289157. DOI: 10.3168/jds.2015-10517.|
|2013||Fritz, S., Capitan, A., Djari, A., Rodriguez, S.C., Barbat, A., Baur, A., Grohs, C., Weiss, B., Boussaha, M., Esquerré, D., Klopp, C., Rocha, D., Boichard, D. :|
|Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2. PLoS One 8:e65550, 2013. Pubmed reference: 23762392. DOI: 10.1371/journal.pone.0065550.|
|2012||Adams, H.A., Sonstegard, T., VanRaden, P.M., Null, D.J., Van Tassell, C., Lewin, H. :|
|Identification of a nonsense mutation in APAF1 that is causal for a decrease in reproductive efficiency in dairy cattle. Plant & Animal Genome (PAG) XX :Abstract P0555, 2012.|
|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.|
|1971||Wijeratne, WVS, Stewart, DL :|
|Population study of abortion in cattle with special reference to genetic factors Animal Production 13:229-235, 1971.|
|1963||Mylrea, P.J. :|
|A suspected genetic cause of abortion in cattle Australian Veterinary Journal 39:35-36, 1963.|
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