A mutation inNFκB interacting protein 1causes cardiomyopathy and woolly haircoat syndrome of Poll Hereford cattle

Cardiomyopathy and woolly haircoat syndrome (CWH) of Poll Hereford cattle is a lethal, autosomal recessive disorder. Cardiac and haircoat changes are congenital, neonatal ocular keratitis develops in some cases and death usually occurs within the first 12 weeks of life. We undertook a homozygosity mapping approach to identify the chromosomal location of the causative gene. Seven candidate genes were examined for homozygosity in affected animals: desmoplakin and junction plakoglobin ( both previously implicated in human cardiocutaneous syndromes), desmocollin 2, desmoglein 2, plakophilin 2, nuclear factor kappa B (NFKB1) and NF kappa B interacting protein 1 (PPP1R13L, also known as NKIP1). Homozygosity in 13 affected animals was observed at the PPP1R13L locus, located on bovine chromosome 18. Subsequent sequence analysis revealed a 7-bp duplication ( c. 956_962dup7) in exon 6 of this 13-exon gene. This frameshift variant is predicted to result in the substitution of three amino acids and the introduction of a premature stop codon at position 325 of the protein product (p.Ser322GlnfsX4). PPP1R13L interacts with NF kappa B, a family of structurally related transcription factors that regulate genes controlling inflammation, immune responses and cell proliferation and survival. CWH represents a large-animal model for cardiocutaneous disorders caused by a mutation in the PPP1R13L gene. The identification of this bovine mutation also indicates that PPP1R13L and other genes affecting NF kappa B activity may be candidate genes in the study of human cardiovascular disease.