Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome.
Tzipora C Falik-ZaccaiYiftah BarsheshetHanna MandelMeital SegevAvraham LorberShachaf GelbergLimor KalfonShani Ben HaroushAdel ShalataLiat Gelernter-YanivSarah ChaimDorith Raviv ShayMorad KhayatMichal WerbnerInbar LeviYishay ShovalGalit TalStavit ShalevEli ReuveniEmily Avitan-HershEugene VlodavskyLiat Appl-SaridDorit GoldsherReuven BergmanZvi SegalOra Bitterman-DeutschOrly AvniPublished in: EMBO molecular medicine (2017)
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 PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l-knocked down murine cardiomyocytes and hearts of Ppp1r13l-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 Ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L 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.
Keyphrases
- inflammatory response
- end stage renal disease
- genome wide
- ejection fraction
- chronic kidney disease
- newly diagnosed
- lps induced
- toll like receptor
- left ventricular
- oxidative stress
- gene expression
- dna methylation
- binding protein
- signaling pathway
- amino acid
- heart failure
- poor prognosis
- genome wide identification
- patient reported outcomes
- immune response
- physical activity
- body mass index
- long non coding rna
- nuclear factor
- small molecule
- induced pluripotent stem cells
- muscular dystrophy