Variant in the 5' untranslated region of insulin-like growth factor 1 receptor is associated with susceptibility to mastitis in cattle.

Mastitis is a common infectious disease of the mammary gland and generates large losses in the dairy industry. By means of positional cloning and functional analysis techniques, we here show that insulin-like growth factor 1 receptor (IGF1R) can possibly mediate susceptibility to mastitis through autophagy. Scanning the whole genome of cows (Bos taurus) that were susceptible or resistant to mastitis in the half-sib families revealed that susceptible cows had a relatively long stretch of cytosine residues (C stretch) in the 5' untranslated region of IGF1R. The forebrain embryonic zinc finger-like (FEZL) transcription factor, which was previously identified as a factor controlling mastitis resistance in the same half-sib families, bound the C stretch of IGF1R. The susceptible type of FEZL with a glycine stretch containing 13 glycines (13G) and the longer C stretch of IGF1R together enhanced expression of IGF1R. Enhancing IGF1R inhibited autophagy in response to Streptococcus agalactiae invasion of mammary epithelial cells, whereas treatment with rapamycin, a known inducer of autophagy, rescued it. Cows carrying the variant combination of 13GFEZL might be more susceptible to mastitis as the result of impaired autophagy. Our results suggest that IGF1R could control innate immunity in mammals and serve as a potential tool for preventing mastitis.