The Generation of Human iPSC Lines from Three Individuals with Dravet Syndrome and Characterization of Neural Differentiation Markers in iPSC-Derived Ventral Forebrain Organoid Model

被引:5
|
作者
Zayat, Valery [1 ]
Kuczynska, Zuzanna [1 ]
Liput, Michal [1 ]
Metin, Erkan [1 ]
Rzonca-Niewczas, Sylwia [2 ]
Smyk, Marta [2 ]
Mazurczak, Tomasz [2 ]
Goszczanska-Ciuchta, Alicja [2 ]
Leszczynski, Pawel [1 ]
Hoffman-Zacharska, Dorota [2 ,3 ]
Buzanska, Leonora [1 ]
机构
[1] Polish Acad Sci, Mossakowski Med Res Inst, Dept Stem Cell Bioengn, PL-02106 Warsaw, Poland
[2] Inst Mother & Child Hlth, Med Genet Dept, PL-01211 Warsaw, Poland
[3] Univ Warsaw, Inst Genet & Biotechnol, Fac Biol, PL-02106 Warsaw, Poland
关键词
SCN1A-related disorders; Dravet syndrome; Panayiotopoulos syndrome; Nav1; 1; haploinsufficiency; stem cell reprogramming; organoids; MOUSE MODEL; SODIUM CURRENT; INTERNEURONS; MUTATIONS; EPILEPSY; NEURONS;
D O I
10.3390/cells12020339
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Dravet syndrome (DRVT) is a rare form of neurodevelopmental disorder with a high risk of sudden unexpected death in epilepsy (SUDEP), caused mainly (>80% cases) by mutations in the SCN1A gene, coding the Nav1.1 protein (alfa-subunit of voltage-sensitive sodium channel). Mutations in SCN1A are linked to heterogenous epileptic phenotypes of various types, severity, and patient prognosis. Here we generated iPSC lines from fibroblasts obtained from three individuals affected with DRVT carrying distinct mutations in the SCN1A gene (nonsense mutation p.Ser1516*, missense mutation p.Arg1596His, and splicing mutation c.2589+2dupT). The iPSC lines, generated with the non-integrative approach, retained the distinct SCN1A gene mutation of the donor fibroblasts and were characterized by confirming the expression of the pluripotency markers, the three-germ layer differentiation potential, the absence of exogenous vector expression, and a normal karyotype. The generated iPSC lines were used to establish ventral forebrain organoids, the most affected type of neurons in the pathology of DRVT. The DRVT organoid model will provide an additional resource for deciphering the pathology behind Nav1.1 haploinsufficiency and drug screening to remediate the functional deficits associated with the disease.
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页数:14
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