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ResearchIn-Press PreviewCell biologyDermatologyGenetics Open Access | 10.1172/JCI195732

TFIIH-p52∆C defines a ninth xeroderma pigmentosum complementation-group XP-J and restores TFIIH stability to p8-defective trichothiodystrophy

Yuka Nakazawa,1 Lin Ye,1 Yasuyoshi Oka,2 Hironobu Morinaga,2 Kana Kato,2 Mayuko Shimada,2 Kotaro Tsukada,2 Koyo Tsujikawa,2 Yosuke Nishio,2 Hiva Fassihi,3 Shehla Mohammed,3 Alan R. Lehmann,3 and Tomoo Ogi2

1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

Find articles by Nishio, Y. in: PubMed | Google Scholar |

1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

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1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

Find articles by Mohammed, S. in: PubMed | Google Scholar

1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

Find articles by Lehmann, A. in: PubMed | Google Scholar

1Department of Molecular Genetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

3National Xeroderma Pigmentosum Service, Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London, United Kingdom

Find articles by Ogi, T. in: PubMed | Google Scholar

Published September 9, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI195732.
Copyright © 2025, Nakazawa et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 9, 2025 - Version history
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Abstract

Few drugs are available for rare diseases due to economic disincentives. However, tailored medications for extremely-rare disorders (N-of-1) offer a ray of hope. Artificial antisense oligonucleotides (ASOs) are now best known for their use in spinal muscular atrophy (SMA). The success of nusinersen/Spinraza for SMA indicates ASO-therapies' potential for other rare conditions. We propose a strategy to develop N-of-1 ASOs for treating one form of trichothiodystrophy (TTD), a rare condition with multisystem abnormalities and reduced life expectancy, associated with instability and greatly reduced amounts of the DNA-repair/transcription factor TFIIH. The therapeutic target carry mutations in GTF2H5, encoding the TFIIH-p8 subunit. This approach was inspired by the diagnosis and molecular dissection of a xeroderma pigmentosum (XP) case with mutations in GTF2H4, encoding the TFIIH-p52 subunit. This is newly classified as a ninth XP complementation-group, XP-J, identified five decades after the discovery of the other XP complementation-groups. The p8-p52 interaction is required to support the TFIIH-complex formation, and the patient's p52 C-terminal truncation results in the complete absence of p8 in TFIIH. However, intriguingly, TFIIH remained stable in vivo, and the XP-J patient did not exhibit any TTD-features. The aim of our ASO-design is to induce a C-terminal truncation of p52 and we have successfully stabilised TFIIH in p8-deficient TTD-A patient cells.

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  • Version 1 (September 9, 2025): In-Press Preview
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