3 research outputs found
Sequence variation in PPP1R13L results in a novel form of cardioâcutaneous syndrome
Dilated cardiomyopathy (DCM) is a lifeâthreatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4â30 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 PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patientsâ fibroblasts and PPP1R13Lâknocked down human fibroblasts presented higher expression levels of proâinflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13lâknocked down murine cardiomyocytes and hearts of Ppp1r13lâdeficient mice. The hypersensitivity to lipopolysaccharide was NFâÎșBâdependent, and its inducible binding activity to promoters of proâinflammatory cytokine genes was elevated in patientsâ fibroblasts. RNA sequencing of Ppp1r13lâknocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13lâdeficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomalârecessive cardioâcutaneous 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