Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.
Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.
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作者：
从患有确定的遗传疾病的患者中产生重编程诱导多能干细胞（iPSC）有望成为了解复杂疾病病因和开发新型治疗干预措施的重要途径。我们已经从LEOPARD综合征患者中产生了iPSC（LS;其主要特征的缩写：小扁豆、心电图异常、眼距增宽、肺动脉瓣狭窄、生殖器异常、生长迟缓和耳聋），属于相对普遍的一类遗传性RAS-MAPK信号传导疾病的常染色体显性发育障碍，其还包括努南综合征（NS），对几种组织和器官系统具有多形效应。患者来源的细胞在PTPN 11基因中具有突变，该基因编码SHP 2磷酸酶。iPSC已被广泛表征并产生多种分化的细胞谱系。LEOPARD综合征患者的主要疾病表型是肥厚型心肌病。我们表明，与来自人胚胎干细胞（HESC）或来自LS患者之一的健康兄弟的野生型（wt）iPSC的心肌细胞相比，来自LS-iPSC的体外衍生心肌细胞更大，具有更高程度的肌节组织化和NFATc 4在细胞核中的优先定位。这些特征与潜在的肥大状态相关。我们还提供了可能促进疾病表型的信号通路的分子见解。
Generation of reprogrammed induced pluripotent stem cells (iPSC) from patients with defined genetic disorders promises important avenues to understand the etiologies of complex diseases, and the development of novel therapeutic interventions. We have generated iPSC from patients with LEOPARD syndrome (LS; acronym of its main features: Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary valve stenosis, Abnormal genitalia, Retardation of growth and Deafness), an autosomal dominant developmental disorder belonging to a relatively prevalent class of inherited RAS-MAPK signaling diseases, which also includes Noonan syndrome (NS), with pleiomorphic effects on several tissues and organ systems. The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSC have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro-derived cardiomyocytes from LS-iPSC are larger, have a higher degree of sarcomeric organization and preferential localization of NFATc4 in the nucleus when compared to cardiomyocytes derived from human embryonic stem cells (HESC) or wild type (wt) iPSC derived from a healthy brother of one of the LS patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signaling pathways that may promote the disease phenotype.
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影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
SHP2敲低和NOONAN/LEOPARD突变体SHP2诱导的胃部缺陷。
影响因子：
4.5
作者：
Jopling, Chris;van Geemen, Daphne;den Hertog, Jeroen
通讯作者：
den Hertog, Jeroen
影响因子：
20.3
作者：
Mikkola, HKA;Fujiwara, Y;Orkin, SH
通讯作者：
Orkin, SH
影响因子：
20.3
作者：
Tartaglia, M;Martinelli, S;Biondi, A
通讯作者：
Biondi, A
影响因子：
3.5
作者：
Oishi, Kimihiko;Zhang, Hui;Gelb, Bruce D.
通讯作者：
Gelb, Bruce D.