Mutations inOvis ariesTMEM154are associated with lower small ruminant lentivirus proviral concentration in one sheep flock

Abstract

Small ruminant lentivirus (SRLV), also called ovine progressive pneumonia virus or maedi-visna, is present in 24% of US sheep. Like human immunodeficiency virus, SRLV is a macrophage-tropic lentivirus that causes lifelong infection. The production impacts from SRLV are due to a range of disease symptoms, including pneumonia, arthritis, mastitis, body condition wasting and encephalitis. There is no cure and no effective vaccine for preventing SRLV infection. However, breed differences in prevalence and proviral concentration indicate a genetic basis for susceptibility to SRLV. Animals with high blood proviral concentration show increased tissue lesion severity, so proviral concentration represents a live animal test for control post-infection in terms of proviral replication and disease severity. Recently, it was found that sheep with two copies of TMEM154 haplotype 1 (encoding lysine at position 35) had lower odds of SRLV infection. In this study, we examined the relationship between SRLV control post-infection and variants in two genes, TMEM154 and CCR5, in four flocks containing 1403 SRLV-positive sheep. We found two copies of TMEM154 haplotype 1 were associated with lower SRLV proviral concentration in one flock (P < 0.02). This identified the same favorable diplotype for SRLV control post-infection as for odds of infection. However, frequencies of haplotypes 2 and 3 were too low in the other three flocks to test. The CCR5 promoter deletion did not have consistent association with SRLV proviral concentration. Future work in flocks with more balanced allele frequencies is needed to confirm or refute TMEM154 association with control of SRLV post-infection.

First survey on association of TMEM154 and CCR5 variants with serological maedi-visna status of sheep in German flocks

“…Two TMEM154 haplotypes, both carrying a nucleotide coding for glutamate (E) at amino acid position 35 of the TMEM154 protein were associated with susceptibility to SRLV infection (as determined by the serological MV status of sheep), whereas a third haplotype, carrying a nucleotide coding for lysine (K) at position 35 was not [ 19 ]. This association was confirmed in additional cohorts in the same and in other studies [ 20 , 21 ], but to our knowledge until now has not been tested in sheep populations outside of North America.…”

Etiology, Epizootiology and Control of Maedi-Visna in Dairy Sheep: A Review

“…Also, the haplotype responsible for the susceptibility seems to be dominant against the "resistant" haplotype [74]. Although there is indication for association between TMEM154 mutations and control of MVV infection, there is no proven association for all the haplotypes [73]. Other genes associated with virus susceptibility are the DPPA2 (Developmental Pluripotency Associated 2)/DPPA4 (Developmental Pluripotency Associated 4), SYTL3 (Synaptotagmin-Like 3), CCR5 (Chemokine receptor 5), MHC (Major Histocompatability Complex), TLR7, TLR8, TLR9 (Toll-like receptors) genes, and APOBEC3 (Apolipoprotein B mRNA-editing enzyme) proteins [75][76][77], whereas the zinc finger cluster, C19orf42 (Chromosome 19 Open Reading Frame 19)/TMEM38A (Transmembrane Protein 38A) and DLGAP1 (Discs Large (Drosophila) Homolog-Associated Protein 1) genes may be used in genetic selection programs to facilitate the control of the disease [78].…”

“…Different alleles of the cellular TMEM154 (Transmembrane protein 154) gene have been found to be associated with the occurrence of MV. Haplotypes carrying nucleotide sequences that code for the amino acid glutamate at position 35 are associated with increased susceptibility to MV, whereas haplotypes carrying nucleotide sequences that code for lysine at the same position are associated with resistance to MV [72][73][74]. Also, the haplotype responsible for the susceptibility seems to be dominant against the "resistant" haplotype [74].…”

Estudio de la patogenia el Maedi-Visna ovino y su aplicación en el diagnóstico y control de la enfermedad = Study of ovine Maedi-Visna pathogenia and its application in diagnostic and illness control

“…Se ha descrito el gen de la proteína transmembrana TMEM154 como posible factor de resistencia frente a los LVPR (Heaton et al, 2012;Alshanbari et al, 2014;Clawson et al, 2015). Aunque no se conoce actualmente el papel de dicha proteína, se ha observado una elevada expresión de la misma en monocitos y linfocitos B, lo que sugiere que podría tener importancia inmunológica (Heaton et al, 2012;Stonos et al, 2014).…”

“…Un estudio reciente ha demostrado una mayor frecuencia de la mutación de dicho gen en las razas Dalsebred, Herdwick y Rough Fells asociada a resistencia genética frente a LVPR (Bowles et al, 2014). Así mismo se ha observado en un rebaño ovino que la presencia de dos copias del halotipo 1 de TMEM154 se asocia a una menor carga proviral (Alshanbari et al, 2014). Por otra parte, el gen TMEM38A se ha asociado a resistencia genética y la dipeptide-binding protein (DPPA) 2 a susceptibilidad frente a LVPR (White et al, 2012).…”