OMIA:001827-9913 : Haplotype with homozygous deficiency MH1 in Bos taurus (taurine cattle)

Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602133 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific symbol: MH1

Mapping: By analysing Illumina Bovine 50k Beadchip genotype data from 47,878 Holstein, 16,833 Montbéliarde and 11,466 Normande cattle in the French genomic selection database, Fritz et al. (2013) identified 34 common (>1%) haplotypes that have a significant deficit (P<10^-4) of homozygotes in live animals, and which are, therefore, each likely to harbour a deleterious mutation. Three of these haplotypes, namely BY (Brachyspina; OMIA 000151-9913), HH1 (OMIA 000001-9913) and HH3 (OMIA 001824-9913), had been reported by VanRaden et al. (2011; J Dairy Sci 94:6153-61). Following the convention of naming such haplotypes with a first letter indicating breed, a second letter H for haplotype, followed by a sequential number, Fritz et al. (2013) named their 14 new Holstein haplotypes as HH4 to HH17, their 11 Montbéliarde haplotypes as MH1 to MH11, and their six Normande haplotypes as NH1 to NH6. Analyses of reproductive data indicated that nine of the 34 haplotypes have a significant effect on fertility, including six of the newly identified haplotypes, namely HH4, HH5, HH6, MH1, MH2 and NH5. This present OMIA entry is for MH1, which is located in chromosome BTA19, at 27.6–29.4Mb (UMD 3.1 genome assembly) (Fritz et al., 2013).

Molecular basis: For eight of the nine haplotypes with a significant effect on calving rate (see Mapping section), Fritz et al. (2013) searched for causal mutations via whole-genome sequence data from 25 Holstein, 11 Montbéliarde and nine Normande bulls which had made major contributions to their breed. Specifically, they filtered "for mutations that were (a) located at+or –6 Mb from the detected haplotype (b) carried in the heterozygous state by the carrier bulls and (c) absent from the non carrier bulls from the three breeds" and then examined identified polymorphisms for their likely effect on protein structure and function. For MH1, Fritz et al. (2013) provided strong evidence for a candidate causal mutation, namely a nonsense mutation (g.27956790C>T; UMD 3.1 genome assembly) in the SHBG gene (which encodes sex-hormone binding globulin), leading to p.Q52X. Reinartz and Distl (2016) reported this mutant occurring in Vorderwald cattle with Montbéliarde ancestry, including in one live animal that is homozygous for this mutant. The one live animal homozygous for this supposedly lethal variant reported by Reinartz and Distl (2016) was reinforced by an extensive study by Michot et al. (2017) who, in the results of genotyping 128,743 Montbéliarde cattle, "identified 242 homozygous carriers for the SHBG nonsense mutation (for 650 expected homozygotes), suggesting that it was not the causative mutation for MH1-linked embryonic lethality." Subsequent fine mapping of the MH1 region excluded SHBG as a candidate and eventually led Michot et al. (2017) to "g.28511199C>T (rs455876205) . . . PFAS p.R1205C" as the likely causal variant. Supporting evidence included "The absence of homozygous mutants among tens of thousands of genotyped animals, the perfect conservation of the affected residue among eukaryotes, and the critical function of PFAS and of the de novo purine synthesis pathway".

Clinical features: The effect of this haplotype is a reduction of 5.8% in heifer calving rate and of 4.84% in cow calving rate (Fritz et al., 2013).

Prevalence: The MH1 haplotype occurs with a frequency of 9.0% in the 16,833 Montbéliarde adult cattle sampled by Fritz et al. (2013), but never as a homozygote. Reinartz and Distl (2020) "genotyped 354 Vorderwald cattle for the PFAS variant, resulting in 41 heterozygous individuals and a T allele frequency of 0.058." They also reported that "The earliest animal with a heterozygous PFAS genotype was 1 of 5 migrant Montbéliarde bulls, and this bull was the most likely origin of the deleterious PFAS allele in Vorderwald cattle. All Vorderwald cattle under study born before introgression of this Montbéliarde bull were homozygous wild type. In addition, all 41 heterozygous Vorderwald cattle had genetic contributions from this Montbéliarde bull, whereas in 74 Vorderwald cattle without genes from Montbéliarde bulls, the PFAS T allele was not observed. In a sample of actual German Fleckvieh the PFAS T allele could be found at a very low frequency."

Breeds: Montbéliarde (Cattle) (VBO_0000306), Vorderwälder, Germany (Cattle) (VBO_0004645).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PFAS phosphoribosylformylglycinamidine synthase Bos taurus 19 NC_037346.1 (27880011..27899172) PFAS 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 Year Published PubMed ID(s) Acknowledgements
820 Montbéliarde (Cattle) Vorderwälder, Germany (Cattle) Abortion due to haplotype MH1 PFAS missense Naturally occurring variant ARS-UCD1.2 19 g.27895397C>T c.3613C>T p.(R1205C) rs455876205 2017 28803020 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2020). OMIA:001827-9913: Online Mendelian Inheritance in Animals (OMIA) [dataset].


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.

2020 Reinartz, S., Distl, O. :
Short communication: Lethal mutations in Vorderwald cattle through Montbéliarde incrossings. J Dairy Sci 103:613-618, 2020. Pubmed reference: 31733870. DOI: 10.3168/jds.2019-17213.
2017 Michot, P., Fritz, S., Barbat, A., Boussaha, M., Deloche, M.C., Grohs, C., Hoze, C., Le Berre, L., Le Bourhis, D., Desnoes, O., Salvetti, P., Schibler, L., Boichard, D., Capitan, A. :
A missense mutation in PFAS (phosphoribosylformylglycinamidine synthase) is likely causal for embryonic lethality associated with the MH1 haplotype in Montbéliarde dairy cattle. J Dairy Sci 100:8176-8187, 2017. Pubmed reference: 28803020. DOI: 10.3168/jds.2017-12579.
2016 Reinartz, S., Distl, O. :
Validation of deleterious mutations in Vorderwald cattle. PLoS One 11:e0160013, 2016. Pubmed reference: 27472836. DOI: 10.1371/journal.pone.0160013.
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.

Edit History

  • Created by Frank Nicholas on 14 Jun 2013
  • Changed by Frank Nicholas on 14 Jun 2013
  • Changed by Frank Nicholas on 04 Aug 2016
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  • Changed by Frank Nicholas on 14 Mar 2020