Publication brief: Xeroderma Pigmentosum: A Model for Premature Ageing

Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder of DNA repair with eight known subtypes, affecting one person per million in the United States and Europe and rising to one per twenty-two thousand people in Japan. XP patients have an impaired nucleotide excision repair (NER) process. For these individuals, DNA damage is often permanent, causing an accelerated process of cell destruction and mutagenesis not commonly seen in the general population until far later in life.

Ageing results from both internal chronologic physiological changes and external exposures, such as UV radiation, pollution and carcinogens. Whereas the consequences of these factors would take decades to visibly present in a healthy individual, due to XP patients’ inability to repair DNA damage, they present with these morbidities from early infancy. Thus, understanding how the cells of XP patients age prematurely provides a unique opportunity to understand the mechanisms of ageing; the topic of focus in Rizza et al.’s 2021 recent article published in the Journal of Investigative Dermatology.

Accumulation of unrepaired DNA in people living with XP leads to a 10,000-fold increased risk of developing skin cancer, with the median age of onset of non-melanoma skin cancer in XP patients during childhood, compared with 60 years in the general population.  This highlights the importance of normally functioning DNA repair in the prevention of cancers. Similarly, peripheral neuropathy occurring in a quarter of XP patients can manifest as a loss of deep tendon reflexes, decreased peripheral sensation, and ataxia. In the general population, 50% of those over 85 years also experience debilitating peripheral neuropathy, characteristically as falls and ataxia. The authors highlight a 2013 study by Suzuki, which showed electrodiagnostic studies and nerve biopsies of peripheral neuropathy in the general population and in patients with XP were similar.

In addition to studying DNA damage mechanisms such as oxidative damage, non-DNA repair pathways can also be studied in an XP model. For example, premature menopause, and thyroid nodules and/or cancer in patients with XP are not fully understood. However, recent studies such as this one published in Nature, by Bidon et al., 2018 have described the importance of XPC protein in pathways outside of DNA repair. XPC deficiency inhibits BRCA1 expression, and a series of downstream cell signalling consequences, ultimately resulting in chromosome instability, is frequently observed in many types of cancers.

Collectively, these insights highlight the wide-ranging effects associated with diminished genomic integrity. By studying XP, we can gain a unique insight into the mechanisms of ageing and how to mitigate its impact. To find out more about our DNA Repair Program and up to date information from our clinical programs, follow us on social media (Facebook, Instagram, LinkedIn, Twitter, YouTube), or visit



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