1:Functional variants in a TTTG microsatellite on 15q26.1 cause familial non-autoimmune thyroid abnormalities.

Nature Genetics.

2024 May;56(5):869-876. doi: 10.1038/s41588-024-01735-5.

Narumi S, Nagasaki K, Kiriya M, Uehara E, Akiba K, Tanase-Nakao K, Shimura K, Abe K, Sugisawa C, Ishii T, Miyako K, Hasegawa Y, Maruo Y, Muroya K, Watanabe N, Nishihara E, Ito Y, Kogai T, Kameyama K, Nakabayashi K, Hata K, Fukami M, Shima H, Kikuchi A, Takayama J, Tamiya G, Hasegawa T.

Genomic DNA is broadly divided into coding regions, which contain the structural information for proteins, and non-coding regions. Non-coding regions account for over 98% of the human genome, but which parts of these regions are involved in hereditary diseases remains largely unknown. In fact, genetic tests covered by insurance only examine the coding regions. In this study, we discovered that base-level changes in a non-coding region of chromosome 15 cause autosomal dominant congenital hypothyroidism. Based on the frequency (1/12,000) in the 38KJPN cohort of the Tohoku Medical Megabank Organization, it is estimated that there are approximately 10,000 patients in Japan alone. This is the most frequent Mendelian disease caused by an abnormality in a non-coding region. Analyzing non-coding regions requires whole-genome sequencing. However, because these regions are so vast, it is statistically difficult to prove a causal relationship between rare DNA sequence changes and disease onset through direct analysis alone. To overcome this challenge, our study adopted an approach that combines linkage analysis with whole-genome sequencing (see figure). We expect that applying a similar approach to hereditary diseases of unknown cause will advance the elucidation of the functions of non-coding regions.

(Satoshi Narumi, Department of Pediatrics, 80th Graduating Class)

Circulation.

26 Apr 2024.doi: 10.1161/CIRCULATIONAHA.123.0648762024

Hideki Kobayashi#, Shugo Tohyama#,*, Hajime Ichimura, Noburo Ohashi, Shuji Chino, Yusuke Soma, Hidenori Tani, Yuki Tanaka, Xiao Yang, Naoko Shiba, Shin Kadota, Kotaro Haga, Taijun Moriwaki, Yuika Morita-Umei, Tomohiko C. Umei, Otoya Sekine, Yoshikazu Kishino, Hideaki Kanazawa, Hiroyuki Kawagishi, Mitsuhiko Yamada, Kazumasa Narita, Takafumi, Naito, Tatsuichiro Seto, Koichiro Kuwahara, Yuji Shiba* and Keiichi Fukuda.

Human iPS cells are a promising cell source for cardiac regenerative medicine. However, a major challenge for clinical application has been the occurrence of ventricular arrhythmias following the transplantation of differentiated cardiomyocytes, due to contamination with non-myocardial cells and cardiomyocytes with high automaticity other than ventricular myocytes. In this study, we first produced high-purity ventricular myocytes from clinical-grade human iPS cells using a proprietary clinical-grade culture medium we developed, and then created cardiac spheroids. Next, simulating clinical application, we transported the cardiac spheroids to Shinshu, a 4-hour journey, and transplanted them into the hearts of monkeys with myocardial infarction. We successfully demonstrated that the transplanted cardiomyocytes engrafted and matured over the long term, restoring the monkeys' cardiac function. Furthermore, we revealed that despite a similar level of engraftment, the side effect of post-transplantation ventricular arrhythmia was significantly lower compared to previous reports. This is the first study to show that arrhythmias after transplantation can be suppressed by refining the cardiomyocyte production method. Based on this finding, we are proceeding with transplantation in heart failure patients (four cases to date) in collaboration with a corporate partner. Further development of cardiac spheroid transplantation therapy using human iPS cells is anticipated. This research was conducted as a joint study with the Department of Regenerative Science and Medicine, Shinshu University (Shiba Laboratory).

(Shugo Tohyama, Tokyo Advanced Medical Research Center, Fujita Health University, 85th Graduating Class)