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

Abstract

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 NFkappaB 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 NFkappaB, 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 NFkappaB activity may be candidate genes in the study of human cardiovascular disease.

iASPP is a novel autophagy inhibitor in keratinocytes

“…In addition to the EOB, wavy fur and cardiac phenotypes that were characterized previously, woe2 mice also exhibit defects in the development of the anterior segment of the eye and the absence of meibomian glands (Toonen et al, 2012). The cattle that harbor a frame-shift mutation in bovine PPP1R13L also exhibit cardiomyopathy and a woolly hair coat (Simpson et al, 2009).…”

“…iASPP is expressed predominantly in epithelial cells, in the skin, testis, heart and stomach (Herron et al, 2005). Mutations in PPP1R13L cause abnormalities of the heart, skin and hair, in both mice and cattle (Herron et al, 2005;Simpson et al, 2009;Toonen et al, 2012). Mice of the wa3 phenotype (which carry a 14-bp deletion in Ppp1r13l, resulting in a loss of the SH3-domain at the C-terminal end of the protein) display wavy hair and open eyelids at birth (EOB), and they develop a rapidly progressive cardiomyopathy (Herron et al, 2005).…”

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

“…To understand why iASPP deficiency causes cardiomyopathy in mice and cattle (7,8), we investigated the cellular distribution of iASPP protein in human and mouse hearts. Interestingly, iASPP was detected at the intercalated discs of fully differentiated cardiomyocytes obtained from human postmortem tissues from unaffected donors and from iASPP wild-type mice (Fig.…”

“…Interestingly, a deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves (6,7) and Wa3 mice (8). However, the molecular Significance Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease that is selective to the right side of the heart and results in heart failure and sudden death.…”

Fatal Arrhythmogenic Right Ventricular Cardiomyopathy in 2 Related Subadult Chimpanzees (Pan troglodytes)

“…10,15 ARVC has also been recognized in dogs, cats, and Polled Hereford cattle. 3,14,46 Although a genetic predisposition is recognized, the pathogenesis of ARVC is not fully understood. This report describes the clinical and pathological features associated with 2 sudden deaths within the captive chimpanzee population at ZSL Whipsnade Zoo in the United Kingdom that closely resemble left-dominant and biventricular variants of ARVC in humans.…”