Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome.
Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome.
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DOI：
10.15252/emmm.201606523
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发表时间：
2017-03
影响因子：
11.1
通讯作者：
Avni O
中科院分区：
文献类型：
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作者：
Falik-Zaccai TC;Barsheshet Y;Mandel H;Segev M;Lorber A;Gelberg S;Kalfon L;Ben Haroush S;Shalata A;Gelernter-Yaniv L;Chaim S;Raviv Shay D;Khayat M;Werbner M;Levi I;Shoval Y;Tal G;Shalev S;Reuveni E;Avitan-Hersh E;Vlodavsky E;Appl-Sarid L;Goldsher D;Bergman R;Segal Z;Bitterman-Deutsch O;Avni O
扩张型心肌病(DCM)是一种威胁生命的疾病，其遗传基础是异质性的，大多未知。来自四个家庭的五名4-30个月大的阿拉伯基督教婴儿被诊断出患有扩张型心肌炎，并伴有轻微的皮肤、牙齿和头发异常。在三名婴儿和另外两名婴儿的母亲中发现了一种纯合子序列变异，在编码iASPP蛋白的PPP1R13L处产生了提前终止密码子。患者的成纤维细胞和PPP1R13L敲除的人成纤维细胞对脂多糖的反应显示出更高水平的促炎细胞因子基因的表达，以及Ppp1r13l敲除的小鼠心肌细胞和Ppp1r13l缺陷小鼠的心脏。患者成纤维细胞对脂多糖的超敏反应依赖于NF-κB，其与促炎细胞因子基因启动子的诱导结合活性增强。对Ppp1r13l敲除的小鼠心肌细胞和来自Ppp1r13l缺陷小鼠不同发育阶段的心脏的RNA测序表明，iASPP在抑制心脏炎症反应中起着关键作用。我们的结果确定PPP1R13L是人类一种新的常染色体隐性遗传性心皮综合征的基础基因，并强烈表明婴儿时期致命的DCM是未能调节心脏对常见炎症应激源的阈值反应所必需的转录途径的结果。
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.