Nature. 2014 Mar 6;507(7490):99-103. doi: 10.1038/nature12923. Epub 2014 Jan 12.

Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells.

Bershteyn M¹, Hayashi Y², Desachy G³, Hsiao EC⁴, Sami S⁵, Tsang KM³, Weiss LA³, Kriegstein AR⁶, Yamanaka S⁷, Wynshaw-Boris A⁸.

Author information

1: 1] Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA [3].
2: 1] Gladstone Institute of Cardiovascular Disease, San Francisco, California, 94158, USA [2] Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, California 94158, USA [3].
3: Department of Psychiatry, Institute for Human Genetics, University of California, San Francisco, California 94143, USA.
4: Division of Endocrinology and Metabolism and Institute for Human Genetics, Department of Medicine, University of California, San Francisco, California 94143, USA.
5: 1] Gladstone Institute of Cardiovascular Disease, San Francisco, California, 94158, USA [2] Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, California 94158, USA.
6: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA.
7: 1] Gladstone Institute of Cardiovascular Disease, San Francisco, California, 94158, USA [2] Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, California 94158, USA [3] Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA [4] Department of Reprogramming Science, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
8: 1] Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, California 94143, USA [2] Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.

Abstract

Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation. Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions. Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate. The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of 'chromosome therapy' to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease.