Title:

Molecular Biology and Human Genomics of Genome Instability Syndromes

 

Speaker:

Tomoo Ogi

Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University

 

Abstract:

Genome instability syndromes arise from deficiencies in DNA repair and DNA damage response pathways. Increasing evidence suggests that disruptions in transcription and DNA damage response mechanisms play a crucial role in the pathogenesis of rare diseases, particularly neurological disorders.

Our previous research has demonstrated that impaired transcription-coupled nucleotide excision repair (TC-NER) directly contributes to neurodegeneration, as seen in Cockayne syndrome. We also identified that digenic mutations in aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 5 (ADH5) impair the detoxification of endogenous formaldehyde, a reactive aldehyde known to cause DNA damage, leading to a novel multisystem disorder known as AMeD syndrome, characterized by neurological symptoms such as developmental delay and intellectual disability.

In parallel, through national genome initiatives such as the Initiative on Rare and Undiagnosed Diseases (IRUD) and the Japan Leading Project for Rare Disease Whole-Genome Sequencing (RDWGS), we have established one of Japan’s most advanced multi-omics analysis environments. With the installation of two Revio sequencing platforms, we launched a dedicated long-read sequencing analysis center. Utilizing long-read whole-genome sequencing and long-read RNA sequencing (ISO-Seq), we are uncovering novel insights into genomic structural variants associated with various neurological diseases.

Additionally, for ultra-rare conditions, we are actively engaged in the N-of-1 program not only for diagnosis but also for drug discovery. By integrating genomic, transcriptomic, and proteomic data, we are investigating the potential of antisense oligonucleotides (ASOs) as a therapeutic modality.

In this lecture, I will present our recent basic research findings, along with the latest advances in rare disease research enabled by long-read sequencing technologies.

 

References:

1. Oka Y, Nakazawa Y, Shimada M, Ogi T. Endogenous aldehyde-induced DNA-protein crosslinks are resolved by transcription-coupled repair. Nature Cell Biology 26(5): 784-796 (2024)
2. Senju C*, Nakazawa Y*, Oso T*, Shimada M, Kato K, Matsuse M, Tsujimoto M, Masaki T, Miyazaki Y, Fukushima S, Tateishi S, Utani A, Murota H, Tanaka K, Mitsutake N, Moriwaki S, Nishigori C, Ogi T. Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum. Proceedings of the National Academy of Sciences of USA 120(27): e2217423120 (2023).
3. Oka Y, Hamada M, Nakazawa Y, Muramatsu H, Okuno Y, Higasa K, Shimada M, Takeshima H, Hanada K, Hirano T, Kawakita T, Sakaguchi H, Ichimura T, Ozono S, Yuge K, Watanabe Y, Kotani Y, Yamane M, Kasugai Y, Tanaka M, Suganami T, Nakada S, Mitsutake N, Hara Y, Kato K, Mizuno S, Miyake N, Kawai Y, Tokunaga K, Nagasaki M, Kito S, Isoyama K, Onodera M, Kaneko H, Matsumoto N, Matsuda F, Matsuo K, Takahashi Y, Mashimo T, Kojima S, Ogi T. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome. Science Advances 6(51): eabd7197 (2020).
4. Nakazawa Y, Hara Y, Oka Y, Komine O, Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Katoh K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg M, Ogi T. Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair. Cell, 180(6): 1228-1244 (2020).