Abstract
Human induced pluripotent stem cell (hiPSC) technology has widely been used for modeling of various genetic diseases. In the disease-modeling iPSC studies, it is necessary to generate hiPSC lines from peripheral tissues of multiple patients and of multiple age- and sex-matched control individuals in order to minimize the differences in genetic background that can affect the results. However, we can generate disease model-hiPSC line with mutant allele being expressing and normal control-hiPSC line with normal allele being expressing from a patient with an X-linked dominant disease such as Rett syndrome, taking advantage of use of the genetic nature (X-chromosome inactivation) and the hiPSC nature (monoclonal proliferation). Furthermore, it may be a straightforward way to identify drug candidates that normalize or minimize the abnormal features and gene expression patterns by a comparative study between mutant active- and normal active-hiPSC lines. Such drug-screening strategy can also be applicable to more major X-linked recessive disease such as Duchenne muscular dystrophy and Fabry disease by generating hiPSC lines from fibroblasts from the heterozygous females. Therefore, X-linked diseases may be efficient targets for drug screening using hiPSC derived from the patients, since faster drug screening hiPSC studies can be conducted for X-linked diseases compared with autosomal diseases by utilizing the genetic natures and the hiPSC nature.
Highlights
Human induced pluripotent stem cell technology has widely been used for modeling of various genetic diseases
We can generate disease model-Human induced pluripotent stem cell (hiPSC) line with mutant allele being expressing and normal control-hiPSC line with normal allele being expressing from a patient with an X-linked dominant disease such as Rett syndrome, taking advantage of use of the genetic nature (X-chromosome inactivation) and the hiPSC nature
It may be a straightforward way to identify drug candidates that normalize or minimize the abnormal features and gene expression patterns by a comparative study between mutant active- and normal active-hiPSC lines. Such drug-screening strategy can be applicable to more major X-linked recessive disease such as Duchenne muscular dystrophy and Fabry disease by generating hiPSC lines from fibroblasts from the heterozygous females
Summary
Human induced pluripotent stem cell (hiPSC) technology has widely been used for modeling of various genetic diseases, especially neurological disorders, in which the target brain tissue is difficult to obtain from the patients [1,2]. We generated iPSC from the skin fibroblast cell lines from the two patients using standard methods and transduction of OCT4-, SOX2-, KLF4- and c-MYC- containing retroviruses [6], and found extremely nonrandom XCI patterns in the majority of iPSC colonies due to monoclonal proliferation of iPSC cells as previously reported [7]. Based on such XCI phenomenon, we successfully obtained two types of iPSC line from the patients: the line with X chromosome harboring the maternally-derived normal MECP2 allele being active and the line with X chromosome harboring the paternallyderived mutant MECP2 allele being active (Figure 1). This may be an advantage of X-linked diseases to autosomal diseases for identification of the disease-specific phenotypes
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