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Research LetterDermatologyGenetics
Open Access | 
10.1172/JCI195731
XP-J, a ninth xeroderma pigmentosum complementation group, results from mutations in GTF2H4, encoding TFIIH-p52 subunit
Hiva Fassihi,1 Shehla Mohammed,1 Yuka Nakazawa,2,3 Heather Fawcett,4 Sally Turner,1 Joanne Palfrey,1 Isabel Garrood,1 Adesoji Abiona,1 Ana M.S. Morley,1 Mayuko Shimada,3 Kana Kato,3 Alan R. Lehmann,1,4 and Tomoo Ogi3,5
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Fassihi, H. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
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1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
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1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Fawcett, H. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Turner, S. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
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1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Garrood, I. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Abiona, A. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Morley, A. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Shimada, M. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Kato, K. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Lehmann, A. in: PubMed | Google Scholar
1National Xeroderma Pigmentosum Service, Rare Disease Centre, Guy’s and St Thomas’ NHS Trust, London, United Kingdom.
2Department of Molecular Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
4Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
5Rare Disease Genome Centre, Nagoya University, Nagoya, Japan.
Address correspondence to: Tomoo Ogi, Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601 Japan. Phone: 81.52.789.3875; Email: togi@riem.nagoya-u.ac.jp.
Authorship note: H Fassihi, SM, YN, and H Fawcett are co–first authors. ARL and TO contributed equally to this work.
Find articles by Ogi, T. in: PubMed | Google Scholar
Published September 9, 2025 - More info
J Clin Invest. 2025;135(22):e195731. https://doi.org/10.1172/JCI195731.
© 2025 Fassihi 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/.
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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 the potential of ASO therapies 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 targets 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 5 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 patient with XP-J 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 stabilized TFIIH in p8-deficient cells from patients with TTD-A.
Authors
Yuka Nakazawa, Lin Ye, Yasuyoshi Oka, Hironobu Morinaga, Kana Kato, Mayuko Shimada, Kotaro Tsukada, Koyo Tsujikawa, Yosuke Nishio, Hiva Fassihi, Shehla Mohammed, Alan R. Lehmann, Tomoo Ogi
Abstract
DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers — Fassihi et al. and Nakazawa et al. — describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies’ characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.
Authors
Arjan F. Theil, Jan H.J. Hoeijmakers
To the editor: Xeroderma pigmentosum (XP) is a genodermatosis, characterised by sun-induced pigmentation and increased skin-cancer risk due to defective DNA repair (1, 2). XP was first described by Kaposi and Hebra in 1874, but its cellular- and molecular-basis began to emerge in the 1960s. Cell-fusion complementation assays revealed genetic heterogeneity in XP by showing that fusion of XP-fibroblasts from different patients restored DNA repair (2). This led to the identification of complementation-groups XP-A to XP-G; groups H and I were later discovered to be due to errors (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI195731DS1) (1, 2). Late 20th-century molecular genetics identified the XP-causative genes, XPA-XPG/ERCC5 (Supplemental Table 1) (1, 2). The majority of patients with XP lack nucleotide excision repair (NER), which removes photolesions from the genome (1). NER-defective XP results from impaired photodamage recognition (DDB2/XPE, XPC) or defective incision involving DNA-repair/transcription-factor TFIIH, XPA, and endonucleases. XPB/p89 and XPD are ATPase/helicases of TFIIH, while XPF-ERCC1 and XPG act as 5’- and 3’-endonucleases, respectively (3, 4). XP-variant (XP-V), an NER-proficient form, described in 1971, was later linked to mutations in POLH, encoding DNA polymerase η that bypasses UV photolesions. To date, all XP cases have been classified into eight complementation groups (XP-A to G and V) (1, 2). Here, we report a patient assigned to a ninth complementation-group, XP-J, identified 50-years after the others. The patient exhibits NER-defective XP-features without signs of other NER disorders, such as Cockayne syndrome (CS) or trichothiodystrophy (TTD) (1). Pathogenic mutations in GTF2H4, encoding the TFIIH-p52 subunit (5), likely disrupt its interaction with p8 (4), whose deficiency causes severe TTD-A (1).
XP140BR, a 6-year-old Caucasian girl diagnosed with XP, shows severe photosensitivity, progressive exposed-site lentigines, microcephaly, and mild developmental delay (Figure 1; case report in Supplemental materials). At three months, she developed severe sunburn with minimal sun exposure, followed by recurrent burns despite sun protection. Lentigines appeared on exposed skin (Figure 1, A–D). Phototesting showed a markedly reduced minimum-erythema-dose (MED) (UVB < 0.03 J/cm2), causing persistent erythema and blistering (Figure 1E). She showed no photophobia or ocular changes and had motor and speech delays. Notably, she lacked any defining features of CS or TTD (1).
Figure 1XP140BR: 6-year-old girl with XP-J. (A–D) Microcephaly without enophthalmos; lentigines on face, posterior neck, and dorsum of hands (black arrows). (E) Scar from blistering sunburn 6 months after UVB-phototesting (red box). (F and G) XP140BR cells are NER-deficient. 1BR (normal control), XP140BR (XP-J), XP15BR (XP-A); 20J/m2 UVC-irradiation (F). 15J/m2 UVC-irradiation (G). (H) XP140BR is not complemented by known XP cDNAs, but is rescued by GTF2H4. 20J/m2 UVC-irradiation. Bars and error bars represent means and SEM, respectively, of experiments (n = 3–4, as indicated by the colored circles and their corresponding plots). (I) GTF2H4 structure and mutations. (J) TFIIH-p52 subunit, encoded by GTF2H4, is C-terminally truncated in the patient, but still forms a stable complex. Left, immunoblots of major TFIIH-subunits (SMC3, loading control); Middle, schematic of TFIIH-subunit interactions; Right, XP genes associated with TFIIH-subunits (references in Supplemental Table 1).
We first measured UV-induced DNA repair. Global genome NER (GG-NER) deficiency is typical of all NER-defective XP but not CS cases, while transcription-coupled NER (TC-NER) is impaired in CS, TTD, and most XP-groups except XP-C and XP-E (1, 2). Unscheduled DNA synthesis (UDS) measures GG-NER by quantifying repair DNA synthesis; TC-NER is evaluated by the recovery of RNA synthesis (RRS) after DNA damage (2). XP140BR showed defects in both, indicating GG- and TC-NER deficiencies (Figure 1, F and G), while transcription was not affected (Supporting data values). We presumed the patient carries mutations in one of the NER genes. Lentivirus UDS-complementation assays with each NER-cDNA failed to restore the UDS-defect, indicating that XP140BR does not belong to any known XP complementation group (Figure 1H).
We performed whole-genome-sequencing and identified potentially pathogenic variants in GTF2H4, encoding the TFIIH-p52 subunit (Figure 1I). The first variant, c.138-1G>A, is located at the intron 2–exon 3 boundary, leading to skipping of exon 3. This results in an in-frame deletion (p52Δ47–81aa); however, this product is unstable and undetectable by immunoblot. The second variant, c.1203_1204delinsGAG, is a frameshift-mutation located in exon 13, resulting in a p.Phe403Valfs*3 C-terminal truncation (p52ΔC). The p52ΔC protein is stably expressed and the entire TFIIH complex remains stable, although the amount is slightly reduced (Figure 1J). To determine whether these GTF2H4 variants are XP causative, we performed a UDS lentivirus–complementation assay. The UDS-defect was restored when GTF2H4-cDNA was expressed (Figure 1H). Mutations in GTF2H4 therefore cause NER-defective XP, and XP140BR defines a ninth XP complementation-group. We designate this as XP-J, since XP-H and XP-I were later found to be identical to XP-D and XP-C, respectively. This will prevent confusion with earlier classifications (Supplemental Table 1).
In summary, we designate an XP patient with mutations in GTF2H4 as XP-J, establishing it as a ninth XP complementation group. This marks the first identification of a new XP complementation group in five decades, since XP-G (1973), and 25-years, since the cloning of POLH for XP-V (1999) (references in Supplemental Table 1). This is the first TFIIH-related disorder reported since TTD-A, caused by mutations in GTF2H5 encoding p8 (2004). The patient with XP-J exhibited definitive NER-deficient XP features without neurological symptoms. Notably, the patient lacked TTD features, despite TFIIH-p52 mutations that are expected to disrupt p52 interaction with p8, deficiencies in which cause TTD-A.
In the accompanying paper (6), we describe how truncation of the p52 C-terminal domain, required for the p52-p8 interaction, can compensate for p8 loss and helps prevent the development of severe TTD-A. In that paper, we also present a therapeutic approach using antisense oligonucleotides (ASOs) for mitigating TTD-A by inducing p52 C-terminal truncation, aiming to stabilise the TFIIH complex.
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