Characterization of heterozygous ATTR Tyr114Cys amyloidosis-specific induced pluripotent stem cells
Kenta Ouchi,
Kaori Isono,
Yuki Ohya,
Nobuaki Shiraki,
Masayoshi Tasaki,
Yukihiro Inomata,
Mitsuharu Ueda,
Takumi Era,
Shoen Kume,
Yukio Ando,
Hirofumi Jono
Affiliations
Kenta Ouchi
Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan
Kaori Isono
Department of Transplantation and Paediatric Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan
Yuki Ohya
Department of Transplantation and Paediatric Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan; Department of Pediatric Surgery, Kumamoto Rosai Hospital, 1670 Takehara-cho, Yatsushiro City, Kumamoto Prefecture, 866-0826, Japan
Nobuaki Shiraki
School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori Ward, Yokohama City, Kanagawa Prefecture, 226-8501, Japan
Masayoshi Tasaki
Department of Biomedical Laboratory Sciences, Graduate School of Health Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan; Department of Neurology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan
Yukihiro Inomata
Department of Pediatric Surgery, Kumamoto Rosai Hospital, 1670 Takehara-cho, Yatsushiro City, Kumamoto Prefecture, 866-0826, Japan
Mitsuharu Ueda
Department of Neurology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan
Takumi Era
Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan
Shoen Kume
School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori Ward, Yokohama City, Kanagawa Prefecture, 226-8501, Japan
Yukio Ando
Department of Amyloidosis Research, Nagasaki International University, 2825-7 Huis Ten Bosch Cho, Sasebo City, Nagasaki Prefecture, 859-3298, Japan
Hirofumi Jono
Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan; Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan; Corresponding author. Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan.
Hereditary transthyretin (TTR) amyloidosis (ATTRv amyloidosis) is autosomal dominant and caused by mutation of TTR gene. Heterozygous ATTR Tyr114Cys (p.Tyr134Cys) amyloidosis is a lethal disease with a life expectancy of about 10 years after onset of the disease. However, the molecular pathogenesis of ATTR Tyr114Cys amyloidosis is still largely unknown. In this study, we took advantage of disease-specific induced pluripotent stem (iPS) cells and generated & characterized the heterozygous ATTR Tyr114Cys amyloidosis-specific iPS cells (Y114C iPS cells), to determine whether Y114C iPS cells could be useful for elucidating the pathogenesis of ATTR Tyr114Cys amyloidosis. We successfully differentiated heterozygous Y114C iPS cells into hepatocyte like cells (HLCs) mainly producing TTR protein. On day 27 after differentiation, the expression of hepatocyte maker albumin was detected, and TTR expression was significantly increased in HLCs differentiated from Y114C iPS cells. LC–MS/MS analysis showed that both WT TTR & ATTR Y114C protein were indeed expressed in the HLCs differentiated from Y114C iPS cells. Notably, the number of detected peptides derived from ATTR Y114C protein was lower than that of WT TTR protein, indeed indicating the clinical phenotype of ATTR Tyr114Cys amyloidosis. Taken together, we first reported the heterozygous Y114C iPS cells generated from patient with ATTR Tyr114Cys amyloidosis, and suggested that Y114C iPS cells could be a potential pathological tool, which may contribute to elucidating the molecular pathogenesis of heterozygous ATTR Tyr114Cys amyloidosis.
