Sequence variation in PPP1R13L results 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...
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Springer Nature
2017-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606523 |
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| author | Tzipora C Falik‐Zaccai Yiftah Barsheshet Hanna Mandel Meital Segev Avraham Lorber Shachaf Gelberg Limor Kalfon Shani Ben Haroush Adel Shalata Liat Gelernter‐Yaniv Sarah Chaim Dorith Raviv Shay Morad Khayat Michal Werbner Inbar Levi Yishay Shoval Galit Tal Stavit Shalev Eli Reuveni Emily Avitan‐Hersh Eugene Vlodavsky Liat Appl‐Sarid Dorit Goldsher Reuven Bergman Zvi Segal Ora Bitterman‐Deutsch Orly Avni |
| author_facet | Tzipora C Falik‐Zaccai Yiftah Barsheshet Hanna Mandel Meital Segev Avraham Lorber Shachaf Gelberg Limor Kalfon Shani Ben Haroush Adel Shalata Liat Gelernter‐Yaniv Sarah Chaim Dorith Raviv Shay Morad Khayat Michal Werbner Inbar Levi Yishay Shoval Galit Tal Stavit Shalev Eli Reuveni Emily Avitan‐Hersh Eugene Vlodavsky Liat Appl‐Sarid Dorit Goldsher Reuven Bergman Zvi Segal Ora Bitterman‐Deutsch Orly Avni |
| author_sort | Tzipora C Falik‐Zaccai |
| collection | DOAJ |
| description | 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 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. |
| format | Article |
| id | doaj-art-3bda5fe3b264454bbafad929188d4a0f |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-3bda5fe3b264454bbafad929188d4a0f2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-01-019331933610.15252/emmm.201606523Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndromeTzipora C Falik‐Zaccai0Yiftah Barsheshet1Hanna Mandel2Meital Segev3Avraham Lorber4Shachaf Gelberg5Limor Kalfon6Shani Ben Haroush7Adel Shalata8Liat Gelernter‐Yaniv9Sarah Chaim10Dorith Raviv Shay11Morad Khayat12Michal Werbner13Inbar Levi14Yishay Shoval15Galit Tal16Stavit Shalev17Eli Reuveni18Emily Avitan‐Hersh19Eugene Vlodavsky20Liat Appl‐Sarid21Dorit Goldsher22Reuven Bergman23Zvi Segal24Ora Bitterman‐Deutsch25Orly Avni26Institute of Human Genetics, Galilee Medical CenterFaculty of Medicine in the Galilee, Bar‐Ilan UniversityMetabolic Disease Unit, Rambam Health Care CampusFaculty of Medicine in the Galilee, Bar‐Ilan UniversityRappaport Faculty of Medicine, Technion, Israel Institute of TechnologyFaculty of Medicine in the Galilee, Bar‐Ilan UniversityInstitute of Human Genetics, Galilee Medical CenterInstitute of Human Genetics, Galilee Medical CenterThe Winter Genetic Institute, Bnei Zion Medical CenterPediatric Cardiology Clinic, Bnei Zion Medical CenterInstitute of Human Genetics, Galilee Medical CenterInstitute of Human Genetics, Galilee Medical CenterThe Genetic Institute, Ha'emek Medical CenterFaculty of Medicine in the Galilee, Bar‐Ilan UniversityInstitute of Human Genetics, Galilee Medical CenterInstitute of Human Genetics, Galilee Medical CenterMetabolic Disease Unit, Rambam Health Care CampusRappaport Faculty of Medicine, Technion, Israel Institute of TechnologyFaculty of Medicine in the Galilee, Bar‐Ilan UniversityDepartment of Dermatology, Rambam Health Care CampusRappaport Faculty of Medicine, Technion, Israel Institute of TechnologyDepartment of Pathology, Galilee Medical CenterRappaport Faculty of Medicine, Technion, Israel Institute of TechnologyRappaport Faculty of Medicine, Technion, Israel Institute of TechnologyFaculty of Medicine in the Galilee, Bar‐Ilan UniversityFaculty of Medicine in the Galilee, Bar‐Ilan UniversityFaculty of Medicine in the Galilee, Bar‐Ilan UniversityAbstract 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.https://doi.org/10.15252/emmm.201606523dilated cardiomyopathygeneticsinflammationmyocarditisPPP1R13L |
| spellingShingle | Tzipora C Falik‐Zaccai Yiftah Barsheshet Hanna Mandel Meital Segev Avraham Lorber Shachaf Gelberg Limor Kalfon Shani Ben Haroush Adel Shalata Liat Gelernter‐Yaniv Sarah Chaim Dorith Raviv Shay Morad Khayat Michal Werbner Inbar Levi Yishay Shoval Galit Tal Stavit Shalev Eli Reuveni Emily Avitan‐Hersh Eugene Vlodavsky Liat Appl‐Sarid Dorit Goldsher Reuven Bergman Zvi Segal Ora Bitterman‐Deutsch Orly Avni Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome EMBO Molecular Medicine dilated cardiomyopathy genetics inflammation myocarditis PPP1R13L |
| title | Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome |
| title_full | Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome |
| title_fullStr | Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome |
| title_full_unstemmed | Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome |
| title_short | Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome |
| title_sort | sequence variation in ppp1r13l results in a novel form of cardio cutaneous syndrome |
| topic | dilated cardiomyopathy genetics inflammation myocarditis PPP1R13L |
| url | https://doi.org/10.15252/emmm.201606523 |
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