Truncation of MIMT1 Gene in the PEG3 Domain Leads to Major Changes in Placental Gene Expression and Stillbirth in Cattle.
We previously identified a microdeletion in the maternally imprinted PEG3 domain in cattle that results in loss of paternal MIMT1 expression and causes late-term abortion and stillbirth. The mutation, when inherited from the sire, is semi-lethal for his progeny with 85% mortality. Here we precisely delineate the deletion and describe comparative analyses of fetuses carrying the deletion with wild-type siblings. Global DNA methylation analysis of cotyledon tissue revealed greater global CpG methylation in fetuses with the deletion (P = 0.003). Gene expression microarray analyses identified increased expression of NPSR1A, IL1RN, NOS3, IL4R, ZDHHC22 and SMOC2 in fetuses carrying the deletion and decreased expression of GRID1, PLG and IGF1. Involvement of NPSR1A, IL1RN, NOS3, and IL4R suggest that some form of restriction related to blood supply, perhaps hypoxemia, may play a role in the pathological mechanism. Also imprinted genes known to play a role in mammalian prenatal development, specifically IGF2, DLK1, MEST, AST1, PEG3, APEG3 and H19 showed differential expression. The most striking difference was abundant abnormal expression of the neuropeptide S receptor 1 (NPSR1) gene in placental cotyledon tissue of 7 of 11 MIMT1(Del/WT) fetuses. The similarity of this proportion with the semi-lethal mortality rate suggests that abnormal NPSR1 expression may be linked to death or survival of MIMT1(Del/WT) fetuses. NPSR1 is expressed as two 3'UTR isoforms (A and B) and the isoform A was detected in MIMT1(Del/WT) cotyledons. NPSR1 is normally not expressed in placenta. Its role in the stillbirth phenomenon has yet to be elucidated, but it may provide a useful prognostic indicator.