Sequence variation in results in a novel form of cardio-cutaneous syndrome.

Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at  encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and -knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as -knocked down murine cardiomyocytes and hearts of -deficient mice. The hypersensitivity to lipopolysaccharide was NF-κB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients' fibroblasts. RNA sequencing of -knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in -deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined  as the gene underlying a novel autosomal-recessive cardio-cutaneous syndrome in humans and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors.