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Medicine, Dentistry, and Pharmacy

September 20, 2023

New technology offers hope for reversing symptoms of XP genetic disorder

A research group at Nagoya University in Japan, with collaborators, have used a new technology to identify a genetic abnormality that causes xeroderma pigmentosum (XP)-F, a skin disorder. The researchers treated cells extracted from patients and effectively reversed many cellular phenotypes associated with XP. Their technique may be effective for genetic treatments of other diseases. Their findings were published in the Proceedings of the National Academy of Sciences. 


Although the prevalence of XP worldwide has been estimated to be around four per million people, in Japan it is one per 22,000. The main symptoms include sun sensitivity, freckling, and susceptibility to skin cancers. These manifestations can be influenced by genetic factors and specific gene mutations. Typical XP cases are classified into eight groups from XP-A to XP-G and XP-V. Of these, XP-F is the rarest form worldwide. However, it is the fourth most common in Japan.  


The research group led by Dr. Chikako Senju (she, her), Dr. Yuka Nakazawa (she, her), and Professor Tomoo Ogi (he, him) at Nagoya University performed genetic analysis of cases of XP-F with one of two variants that cause DNA repair deficiency in the non-coding regions of the ERCC4/XPF genes to identify the abnormalities that cause XP.  


“We found that the disease was caused by an abnormal sequence in the intron (non-coding) region of the XPF gene,” said Dr. Ogi. “In the process of transcribing mRNA, only the ‘exon’ region, which contains the information necessary for protein synthesis, is extracted, and the intron region is removed in a process called ‘splicing’.”  


“Patients with the genetic abnormality found in our study have XP because the splicing of the XP-F gene is not carried out properly, so the protein is not produced by transcription,” he continued. “Without the protein, the nucleotide excision repair mechanism, which removes DNA damage caused by UV light, does not function.” 


Their findings suggest that XP can be treated by enabling the normal splicing reaction to take place in the patient's cells. The abnormality identified in the patient is caused by the binding of the splicing factor to the wrong sequence. Therefore, ensuring that the splicing reaction occurs in the normal position could potentially reverse some of the symptoms of XP.  


The group investigated the use of short nucleic acids called antisense oligonucleotides (ASOs) that bind to mRNA and can be used to correct abnormal splicing events. “Remarkably, treatment of patient cells by ASOs designed for the mutations successfully restored production of XP-F protein and DNA repair activity,” said Dr. Nakazawa. “Collectively, our results suggest that ASO-based treatment is an effective therapeutic approach for XP.” 


“This method can be used to simultaneously identify pathogenic mutations that are the cause of any disease and select candidate therapeutic drugs,” said Dr. Ogi. “Importantly, this method can be applied to all genetic diseases, not just XP. In the future, this technology could be used to develop custom treatments for various rare diseases.”


The study, "Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum," was published in the journal Proceedings of the National Academy of Sciences at DOI: 10.1073/pnas.2217423120 



Chikako Senju, Yuka Nakazawa, Taichi Oso, Mayuko Shimada, Kana Kato, Michiko Matsuse, Mariko Tsujimoto, Taro Masaki, Yasushi Miyazaki, Satoshi Fukushima, Satoshi Tateishi, Atsushi Utani, Hiroyuki Murota, Katsumi Tanaka, Norisato Mitsutake, Shinichi Moriwaki, Chikako Nishigori, and Tomoo Ogi


Media Contact:

Matthew Coslett
International Communications Office, Nagoya University



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