Journal Article

Modeling abnormal early development with induced pluripotent stem cells from aneuploid syndromes

Wen Li, Xianming Wang, Wenxia Fan, Ping Zhao, Yau-Chi Chan, Shen Chen, Shiqiang Zhang, Xiangpeng Guo, Ya Zhang, Yanhua Li, Jinglei Cai, Dajiang Qin, Xingyan Li, Jiayin Yang, Tianran Peng, Daniela Zychlinski, Dirk Hoffmann, Ruosi Zhang, Kang Deng, Kwong-Man Ng, Bjorn Menten, Mei Zhong, Jiayan Wu, Zhiyuan Li, Yonglong Chen, Axel Schambach, Hung-Fat Tse, Duanqing Pei and Miguel A. Esteban

in Human Molecular Genetics

Volume 21, issue 1, pages 32-45
Published in print January 2012 | ISSN: 0964-6906
Published online September 2011 | e-ISSN: 1460-2083 | DOI:
Modeling abnormal early development with induced pluripotent stem cells from aneuploid syndromes

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Many human diseases share a developmental origin that manifests during childhood or maturity. Aneuploid syndromes are caused by supernumerary or reduced number of chromosomes and represent an extreme example of developmental disease, as they have devastating consequences before and after birth. Investigating how alterations in gene dosage drive these conditions is relevant because it might help treat some clinical aspects. It may also provide explanations as to how quantitative differences in gene expression determine phenotypic diversity and disease susceptibility among natural populations. Here, we aimed to produce induced pluripotent stem cell (iPSC) lines that can be used to improve our understanding of aneuploid syndromes. We have generated iPSCs from monosomy X [Turner syndrome (TS)], trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome) and partial trisomy 11;22 (Emanuel syndrome), using either skin fibroblasts from affected individuals or amniocytes from antenatal diagnostic tests. These cell lines stably maintain the karyotype of the donors and behave like embryonic stem cells in all tested assays. TS iPSCs were used for further studies including global gene expression analysis and tissue-specific directed differentiation. Multiple clones displayed lower levels of the pseudoautosomal genes ASMTL and PPP2R3B than the controls. Moreover, they could be transformed into neural-like, hepatocyte-like and heart-like cells, but displayed insufficient up-regulation of the pseudoautosomal placental gene CSF2RA during embryoid body formation. These data support that abnormal organogenesis and early lethality in TS are not caused by a tissue-specific differentiation blockade, but rather involves other abnormalities including impaired placentation.

Journal Article.  6175 words.  Illustrated.

Subjects: Genetics and Genomics

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