title: Sequence variation inPPP1R13Lresults in a novel form of cardio-cutaneous syndrome.
abstract: 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 atPPP1R13Lencoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts andPPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well asPpp1r13l-knocked down murine cardiomyocytes and hearts ofPpp1r13l-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 ofPpp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development inPpp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determinedPPP1R13Las 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.
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel falikmd.genetics@gmail.com orly.avni@biu.ac.il.|Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Tzipora C
authors.identifier: 0000-0003-0065-1922
authors.initials: TC
authors.lastname: Falik-Zaccai
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Yiftah
authors.identifier: 0000-0003-0883-8425
authors.initials: Y
authors.lastname: Barsheshet
authors.affiliation: Metabolic Disease Unit, Rambam Health Care Campus, Haifa, Israel.|Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Meital
authors.initials: M
authors.lastname: Segev
authors.affiliation: Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.|Department of Pediatric Cardiology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Lorber
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Shachaf
authors.initials: S
authors.lastname: Gelberg
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Kalfon
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Ben Haroush
authors.affiliation: The Winter Genetic Institute, Bnei Zion Medical Center, Haifa, Israel.
authors.forename: Adel
authors.identifier: 0000-0001-5209-2072
authors.initials: A
authors.lastname: Shalata
authors.affiliation: Pediatric Cardiology Clinic, Bnei Zion Medical Center, Haifa, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Gelernter-Yaniv
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chaim
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Dorith
authors.initials: D
authors.lastname: Raviv Shay
authors.affiliation: The Genetic Institute, Ha'emek Medical Center, Afula, Israel.
authors.forename: Morad
authors.initials: M
authors.lastname: Khayat
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Werbner
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Inbar
authors.initials: I
authors.lastname: Levi
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Yishay
authors.initials: Y
authors.lastname: Shoval
authors.affiliation: Metabolic Disease Unit, Rambam Health Care Campus, Haifa, Israel.|Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Tal
authors.affiliation: Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.|The Genetic Institute, Ha'emek Medical Center, Afula, Israel.
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Reuveni
authors.affiliation: Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Emily
authors.initials: E
authors.lastname: Avitan-Hersh
authors.affiliation: Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.|Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Eugene
authors.initials: E
authors.lastname: Vlodavsky
authors.affiliation: Department of Pathology, Galilee Medical Center, Nahariya, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Appl-Sarid
authors.affiliation: Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.|Department of Diagnostic Imaging, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Goldsher
authors.affiliation: Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.|Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Bergman
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.|Department of Ophthalmology, Galilee Medical Center, Nahariya, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Segal
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.|Dermatology Clinic, Galilee Medical Center, Nahariya, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Bitterman-Deutsch
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel falikmd.genetics@gmail.com orly.avni@biu.ac.il.
authors.forename: Orly
authors.identifier: 0000-0002-9270-9564
authors.initials: O
authors.lastname: Avni
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002675:Child, Preschool; D018389:Codon, Nonsense; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D044542:LEOPARD Syndrome / Q000235:genetics* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C119612:PPP1R13L protein, human; C501916:Ppp1r13l protein, mouse; D012097:Repressor Proteins
keywords: 
  PPP1R13L
  ; dilated cardiomyopathy; genetics; inflammation; myocarditis