A single base pair duplication in the SLC33A1 gene is associated with fetal losses and neonatal lethality in Manech...

We recently discovered that the Manech Tête Rousse (MTR) deficient homozygous haplotype 2 (MTRDHH2) probably carries a recessive lethal mutation in sheep. In this study, we fine-mapped this region through whole-genome sequencing of five MTRDHH2 heterozygous carriers and 95 non-carriers from various ovine breeds. We identified a single base pair duplication within the SLC33A1 gene, leading to a frameshift mutation and a premature stop codon (p.Arg246Alafs*3). SLC33A1 encodes a transmembrane transporter of acetyl-coenzyme A that is crucial for cellular metabolism. To investigate the lethality of this mutation in homozygous MTR sheep, we performed at-risk matings using artificial insemination (AI) between heterozygous SLC33A1 variant carriers (SLC33A1_dupG). Pregnancy was confirmed 15 days post-AI using a blood test measuring interferon Tau-stimulated MX1 gene expression. Ultrasonography between 45 and 60 days post-AI revealed a 12% reduction in AI success compared with safe matings, indicating embryonic/fetal loss. This was supported by the MX1 differential expression test suggesting fetal losses between 15 and 60 days of gestation. We also observed a 34.7% pre-weaning mortality rate in 49 lambs born from at-risk matings. Homozygous SLC33A1_dupG lambs accounted for 47% of this mortality, with deaths occurring mostly within the first 5 days without visible clinical signs. Therefore, appropriate management of SLC33A1_dupG with an allele frequency of 0.04 in the MTR selection scheme would help increase overall fertility and lamb survival.