In other species: chimpanzee , domestic cat

Categories: Immune system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 186940 (gene) , 607750 (gene)

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific name: Resistance/susceptibility to Visna/Maedi virus (VMV); Resistance/susceptibility to ovine progressive pneumonia virus (OPPV)

Species-specific symbol: OPP

Mapping: Using the first-generation ovine 50K SNP chip, Heaton et al. (2012) conducted a GWAS in 69 matched pairs (infected/uninfected controls) of mixed-breed sheep from the USMARC (Nebraska) sheep population. Two SNPs in the same region of chromosome OAR17 showed the highest and third-highest genome-wide significance. In a separate GWAS of "964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes", White et al. (2012) confirmed the TMEM154 results of Heaton et al. (2012) and reported "12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P<1 × 10(-5))".
Riggio et al. (2024) used a "a combined genome-wide approach using a high-density SNP array has been performed, comparing VMV[Visna/Maedi virus]-infected (n = 78) and non-infected (n = 66) individuals of the Valle del Belice breed. ... The comparison among results from different approaches ... revealed two association signals: on OAR03 close to the GRIN2B gene and on OAR05 close to the TMEM232 gene."

Markers: In a global survey of sheep breeds, Heaton et al. (2013) observed "The average frequency of TMEM154 E35 among 74 breeds was 0.51 [which] indicated that highly-susceptible alleles were present in most breeds around the world." They concluded that "The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks."

Molecular basis: Following up the results of their GWAS described above, Heaton et al. (2012) showed that the two OAR17 SNPs are located in "an ovine gene homologous to the human TMEM154 gene". Subsequent sequencing and association analysis showed that "Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection. . . . The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5–1,100). In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36–3.43). Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure." Taken together, these results led to Heaton et al. (2012) concluding that "TMEM154 may play a central role in ovine lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection". While the actual function of the membrane protein encoded by TMEM154 is still to be worked out, the apparent resistance of sheep homozygous for a mutant that results in no functional peptide strongly suggests a mechanism for resistance/susceptibility, namely that the lentivirus needs this peptide in order to infect cells. Following up one of the most promising regions for control of infection from the GWAS of White et al. (2012), White et al. (2013) "identified a small insertion/deletion variant near [5' of] ZNF389 [LOC105603932; OAR20; g.29500068_29500069delAT; GenBank NC_019477.1] that showed consistent association with proviral concentration in three animal sets . . . The best estimate of proviral concentration by genotype, obtained from all 1310 OvLV-positive animals tested, showed insertion homozygotes had less than half the proviral concentration of other genotypes (P < 0.0001). . . . To our knowledge, this is the first genetic variant consistently associated with host control of OvLV post-infection in multiple sheep flocks."

Clinical features: As reported by Heaton et al. (2013), "The first signs of disease typically appear after age two and often include the loss of body condition and indurative mastitis (hard udder). Disease progression is associated with severe clinical signs that include difficulty breathing, chronic wasting, loss of motor control, and arthritis."

Breeds: Columbia (Sheep) (VBO_0001378), Polypay (Sheep) (VBO_0001560), Rambouillet (Sheep) (VBO_0001570).
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 genes: