Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 619136 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific symbol: MH2

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 MH2, which is located in chromosome BTA29, at 27.9–29.1Mb (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 MH2, Fritz et al. (2013) provided strong evidence for a candidate causal mutation, namely a nonsense mutation (g.28879810C>T; UMD 3.1 genome assembly) in the SLC37A2 gene (which solute carrier family 37, member 2), leading to p.R12X. Reinartz and Distl (2016) reported homozygosity of this mutant in an aborted Vorderwald x Montbéliarde crossbred foetus inbred to Montbéliarde bulls. The mutant occurs at a frequency of around 5% in Vorderwald cattle with Montbéliarde ancestry but is absent from Vorderwald cattle with no Montbéliarde ancerstry.

Clinical features: The effect of this haplotype is a reduction of 5.26% in heifer calving rate and of 4.85% in cow calving rate (Fritz et al., 2013).

Prevalence: The MH2 haplotype occurs with a frequency of 7.0% in the 16,833 Montbéliarde adult cattle sampled by Fritz et al. (2013), but only once as a homozygote. Reinartz and Distl (2016): "Among all further 341 Vorderwald cattle genotyped we found 27 SLC37A2:g.28879810C>T heterozygous animals resulting in an allele frequency of 0.0396. Among the 120 male Vorderwald cattle, there were 12 heterozygous with an allele frequency of 0.05. The SLC37A2:g.28879810C>T mutation could not be found in further nine cattle breeds nor in Vorderwald cattle with contributions from Ayrshire bulls. In 69 Vorderwald cattle without genes from Montbéliarde bulls the mutated allele of SLC37A2:g.28879810C>T could not be detected."

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: