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Human Mutations Affecting Reprogramming into Induced Pluripotent Stem Cells

Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

Special Issue: iPS Cell Technologies in Human Diseases

The development of induced pluripotent stem cells (iPSCs) provides unprecedented opportunities for life sciences, drug discovery, and regenerative medicine. iPSCs have been generated from somatic cells in many patients with various genetic diseases carrying specific mutations. However, the efficiency of iPSC generation is quite low. Less than 1% of human primary somatic cells can usually turn into iPSCs. Previous studies have revealed that cellular signaling pathways, epigenetic status, and cellular senescence were major barriers to iPSC generation. Serendipitously in some cases, human mutations themselves affect the reprogramming efficiency of iPSC generation as well as cellular phenotypes recapitulating their disease symptoms. Mutations, which cause altered DNA repair (e.g., Ataxia-Telangiectasia, fanconi anemia and DNA Ligase IV (LIG4) syndrome), premature aging (e.g., Hutchinson–Gilford progeria syndrome and Néstor–Guillermo progeria syndrome), altered telomere homeostasis (e.g., dyskeratosis congenita), mitochondrial respiratory dysfunction, chromosomal abnormalities, and fibrodysplasia ossificans progressiva, have all been shown to affect the reprogramming efficiency of somatic cells to iPSCs. In this review, the effects of such mutations are summarized and the methods which have been employed to rescue efficient iPSC generation from mutant cells is discussed. Although the mutations affecting reprogramming processes are rare, these mutations have been invaluable to the elucidation of reprogramming mechanisms and to the development of improved reprogramming technologies.
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