Xeroderma Pigmentosum Patients Research Articles

106 XPC splice site founder mutation in families with xeroderma pigmentosum from Dominican Republic and Honduras

Xeroderma pigmentosum (XP) is a rare autosomal recessive DNA repair disorder. XP is caused by mutations in 7 nucleotide excision repair genes, XP-A to XP-G, and POLH gene involved in trans lesion synthesis pathway by which cells replicate across UV-induced DNA lesions. XP-C is the most common in the U.S. XP patients are highly sun-sensitive with 10,000-fold increased risk of skin cancer. In a cohort of 123 XP patients and their families enrolled at the National Institutes of Health (NIH), we identified a founder XPC splice site mutation (c.2251-1G>C) in 8 XP patients (4 from the Dominican Republic, 2 from Honduras and 2 from Tanzania). They all had extensive sun exposure with multiple skin cancers and severe ocular damage (blindness or ocular cancer). Seven XP patients were homozygous for the splice mutation and one was a compound heterozygote. Microsatellite analysis surrounding the XPC founder mutation indicates that these patients might share a common ancestor. This splice mutation has been reported as very frequent in parts of Africa (1/5,000 in Mayotte). This African XPC founder mutation may have been brought to the Dominican Republic and Central America as part of the slave trade that flourished in the 16th to 18th centuries. Other founder mutations have been reported in XP patients in Japan (XPA) and Morocco (XPC, TG-deletion). The increase in frequency of XPC founder mutations in Dominican Republic and Honduras would have public health implications. The early detection and rigorous UV protection can improve XP patient clinical outcomes in these countries.

107 Increased prevalence of thyroid nodules in xeroderma pigmentosum patients: A feature of premature aging

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease of DNA repair characterized by severe ultraviolet (UV) sensitivity resulting in a 10,000-fold increased risk for skin cancer. Symptoms include freckle-like pigmentation in sun exposed skin before age 2 years, severe burns after minimal sun exposure (50% of patients) and skin cancers in children. XP is also considered a premature aging disease because of its features such as: dry skin, increased sun-induced freckling in young patients, higher incidence of skin cancers in young patients and premature menopause.

Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. Twenty-seven families were screened for germline variants in eight XP-related genes. All patients (N=32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7years. ERCC2/XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.

Malignant Melanoma in Child with Xeroderma Pigmentosum: A Rare Case

Background: Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by photosensitivity, cutaneous pigmentary changes, and malignant tumor development at an early age. The basic defect underlying the clinical manifestations is nucleotide excision repair defect, leading to defective repair of ultraviolet (UV)-induced DNA. XP patients who are younger than 20 years of age have more than 1000-fold increased risk of developing malignant neoplasms of the skin, which commonly include squamous cell carcinoma, basal cell carcinoma, fibrosarcoma, and malignant melanoma. Malignant melanoma arises in only about 3% of XP patients. Purpose: To report a case of malignant melanoma in a child with XP. Case: A 7-years-old girl presented with multiple hypopigmentation and hyperpigmentation macules since age of two, throughout the body, more on sun-exposed areas. The physical examination showed solitary tumor extensive ulcero- proliferative surface with areas of hemorrhage and blackish pigmentation on the vertex region. Histological examination revealed a feature of nodular malignant melanoma, and the condition became worse after she underwent two cycles of chemotherapy. Discussion: Despite the rare occurrence, the nodular type of malignant melanoma in XP patients is the most aggressive and responsible for the fatal condition. Conclusion: Early detection of XP is necessary due to its fast-growing nature and high metastatic possibility as well as mortality index.

The Iberian legacy into a young genetic xeroderma pigmentosum cluster in central Brazil

In central Brazil, in the municipality of Faina (state of Goiás), the small and isolated village of Araras comprises a genetic cluster of xeroderma pigmentosum (XP) patients. The high level of consanguinity and the geographical isolation gave rise to a high frequency of XP patients. Recently, two founder events were identified affecting that community, with two independent mutations at the POLH gene, c.764 + 1 G > A (intron 6) and c.907 C > T; p.Arg303* (exon 8). These deleterious mutations lead to the xeroderma pigmentosum variant syndrome (XP-V). Previous reports identified both mutations in other countries: the intron 6 mutation in six patients (four families) from Northern Spain (Basque Country and Cantabria) and the exon 8 mutation in two patients from different families in Europe, one of them from Kosovo. In order to investigate the ancestry of the XP patients and the age for these mutations at Araras, we generated genotyping information for 22 XP-V patients from Brazil (16), Spain (6) and Kosovo (1). The local genomic ancestry and the shared haplotype segments among the patients showed that the intron 6 mutation at Araras is associated with an Iberian genetic legacy. All patients from Goiás, homozygotes for intron 6 mutation, share with the Spanish patients identical-by-descent (IBD) genomic segments comprising the mutation. The entrance date for the Iberian haplotype at the village was calculated to be approximately 200 years old. This result is in agreement with the historical arrival of Iberian individuals at the Goiás state (BR). Patients from Goiás and the three families from Spain share 1.8 cM (family 14), 1.7 cM (family 15), and a more significant segment of 4.7 cM within family 13. On the other hand, the patients carrying the exon 8 mutation do not share any specific genetic segment, indicating an old genetic distance between them or even no common ancestry.

Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and inter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. Here we report cryo-electron microscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF helical domain masks the ERCC1 (HhH)2 domain and restricts access to the XPF catalytic site. DNA junction engagement releases the ERCC1 (HhH)2 domain to couple with the XPF-ERCC1 nuclease/nuclease-like domains. Structure-function data indicate xeroderma pigmentosum patient mutations frequently compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations in XPF often display substantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation.

A novel nonsense mutation of ERCC2 in a Vietnamese family with xeroderma pigmentosum syndrome group D

Xeroderma pigmentosum (XP) group D, a severe disease often typified by extreme sun sensitivity, can be caused by ERCC2 mutations. ERCC2 encodes an adenosine triphosphate (ATP)-dependent DNA helicase, namely XP group D protein (XPD). The XPD, one of ten subunits of the transcription factor TFIIH, plays a critical role in the nucleotide-excision repair (NER) pathway. Mutations in XPD that affect the NER pathway can lead to neurological degeneration and skin cancer, which are the most common causes of death in XP patients. Here, we present detailed phenotypic information on a Vietnamese family in which four members were affected by XP with extreme sun sensitivity. Genomic analysis revealed a compound heterozygous mutation of ERCC2 that affected family members and single heterozygous mutations in unaffected family members. We identified a novel, nonsense mutation in one allele of ERCC2 (c.1354C > T, p.Q452X) and a known missense mutation in the other allele (c.2048G > A, p.R683Q). Fibroblasts isolated from the compound heterozygous subject also failed to recover from UV-driven DNA damage, thus recapitulating aspects of XP syndrome in vitro. We describe a novel ERCC2 variant that leads to the breakdown of the NER pathway across generations of a family presenting with severe XP.

Conjunctival melanoma in patients with xeroderma pigmentosum: a series of four cases.

To study the demographic features, treatment, histopathology, and outcomes in patients of xeroderma pigmentosum (XP) with conjunctival melanoma. Retrospective case series. The median age at presentation was 18years (range 9-30years). There were three females and one male patient presenting with a median duration of symptoms of 3months (range 1-60months). The tumor was located in the bulbar conjunctiva in all 4 patients. All patients had corneal involvement by the tumor. The median tumor basal diameter was 7mm (range 4-15mm). Wide tumor excisional biopsy with alcohol keratoepithelectomy, cryotherapy to the free margins, and amniotic membrane grafting was done in three patients. One patient underwent orbital exenteration for extensive tumor. One patient also received adjuvant plaque brachytherapy for microscopic residual tumor. Over a median follow-up of 22months (range 2-101months), there were no recurrences, metastasis, or death. Conjunctival melanoma in XP is rare and manifests at a younger age.

Daylight photodynamic therapy is an option for the treatment of actinic keratosis in patients with xeroderma pigmentosum in Africa.

Xeroderma pigmentosum (XP) is a very rare and severe genetic disorder with a DNA repair defect of ultraviolet (UV)-induced damage. Photodynamic therapy (PDT) has been successfully used in XP patients to treat actinic keratosis (AK) and daylight PDT (DL-PDT) has demonstrated similar efficacy to conventional PDT (C-PDT) for AK. To assess DL-PDT for the treatment of AK in patients with XP. Patients with XP were evaluated by a group of Spanish and African dermatologists. Clinical characteristics of the patients were assessed and divided in mild, severe or moderate affectation of AK in the face. A topical photosensitizer was extended on the patients' faces and after two hours of indoor light exposure, fluorescence was assessed and the cream was removed. Patients were examined two and seven days later to assess the reaction to PDT and followed up three months later. A total of 13 patients were treated on the whole face. Three were classified as severe AK, six as moderate AK and four as mild AK. Fluorescence assessment showed a soft yellow-green colour and a pink-color delineating the AK. Two days after treatment patients presented a scaly reaction. After one week the reaction healed, there was improvement and after three months no adverse events were noticed. PDT is an option for treatment of AK in patients with XP.

Sunlight, Vitamin D, and Xeroderma Pigmentosum.

Sunlight, in particular UV-B radiation, is an important factor for endogenous vitamin D production as 80-90% of the required vitamin D needs to be photosynthesized in the skin. The active form of vitamin D, vitamin D3 or calcitriol, binds to the ligand-activated transcription factor vitamin D receptor (VDR) for genomic and non-genomic effects. Recently, calcitriol and analogs have been shown to have antiproliferative effects in mouse and human BCC and SCC cell lines in vitro. As UV radiation plays a critical role in the photosynthesis of vitamin D, stringent sun protection, as recommended for xeroderma pigmentosum (XP) patients, may impact their vitamin D levels.XP is a rare autosomal recessive disorder with a worldwide prevalence of 1 in 1,000,000. XP can be divided into seven different complementation groups: XP-A to XP-G. The complementation groups correspond with the underlying gene defect. Defects in these genes lead to a defective nucleotide excision repair (NER), which is necessary to remove UV-induced DNA damage such as the UV photoproducts cyclobutane pyrimidine dimers (CPD) and 6-4 pyrimidine-pyrimidone (6-4 PP) dimer. Additionally, a variant form with a mutation in the translational polymerase η gene (PolH), also called XP variant (XPV), exists. Patients with XPV show a defect in translesion synthesis. Due to their inability to repair UV-induced lesions, XP patients exhibit an increased risk for UV-induced nonmelanoma skin cancer (NMSC) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) as well as melanoma. Although no curative therapy for XP exists today, numerous options for the treatment and prophylaxis of skin cancer have become available.

How history and geography may explain the distribution in the Comorian archipelago of a novel mutation in DNA repair-deficient xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) is a rare, genetic, autosomal nucleotide excision repair-deficient disease characterized by sun-sensitivity and early appearance of skin and ocular tumors. Thirty-two black-skinned XP from Comoros, located in the Indian Ocean, were counted, rendering this area the highest world prevalence of XP. These patients exhibited a new homozygous XPC mutation at the 3’-end of the intron12 (IVS 12-1G>C) leading to the absence of XPC protein. This mutation, characteristic of the consanguineous Comorian families, is associated with a founder effect with an estimated age of about 800 years. Analysis of mt-DNA and Y-chromosome identified the haplogroups of patients, who are derived from the Bantu people. Although the four Comorian islands were populated by the same individuals during the 7-10th centuries, XP was found now only in the Comorian island of Anjouan. To avoid the slavery process caused by the arrival of the Arabs around the 11-13th centuries, inhabitants of Anjouan, including XP-heterozygotes, hid inland of the island protected by volcanoes. This population lived with an endogamic style, without connection with the other islands. XP patients still live in the same isolated villages as their ancestries. Local history and geography may, thus, explain the high incidence of XP located exclusively in one island.

Detection of the small oligonucleotide products of nucleotide excision repair in UVB-irradiated human skin

UVB radiation results in the formation of potentially mutagenic photoproducts in the DNA of epidermal skin cells. In vitro approaches have demonstrated that the nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small (∼30-nt-long), excised, damage-containing DNA oligonucleotides (sedDNAs). Though this process presumably takes place in human skin exposed to UVB radiation, sedDNAs have not previously been detected in human skin. Using surgically discarded human skin, we have optimized the detection of the sedDNA products of NER from small amounts of human epidermal tissue ex vivo within minutes of UVB exposure and after UVB doses that normally lead to minimal erythema. Moreover, sedDNA generation was inhibited by treatment of skin explants with spironolactone, which depletes the epidermis of the essential NER protein XPB to mimic the skin of xeroderma pigmentosum patients. Time course experiments revealed that a partially degraded form of the sedDNAs could be readily detected even 12 hours following UVB exposure, which indicates that these repair products are relatively stable in human skin epidermis. Together, these data suggest that sedDNA detection may be a useful assay for determining how genetic, environmental, and other factors influence NER activity in human skin epidermis and whether abnormal sedDNA processing contributes to photosensitive skin disorders.

Facial photoprotection in xeroderma pigmentosum (XP) patients: Validation of a new self-reported questionnaire of adherence.

Adherence to photoprotection is the only way to prevent skin cancers and eye disease in xeroderma pigmentosum (XP). No validated self-report questionnaire exists for assessing adherence to photoprotection practices in individuals with XP. We sought to validate a self-reported measure of adherence to face photoprotection in this population. Sixty six XP patients recruited from the patient list of the XP specialist service in London, UK, completed a questionnaire of adherence to specific photoprotection behaviours. We measured objective ultraviolet radiation (UVR) exposure to the face continuously for 21days with a wristworn UVR electronic dosimeter combined with a daily photoprotection diary. Reliability and convergent validity of the questionnaire were tested in relation to overall UVR exposure, UVR dose to the face, daily photoprotection activities, other self-reported photoprotection practices and clinical ratings of patient's protection. Internal consistency of the questionnaire was satisfactory. Questionnaire total scores were concordant with objective UVR exposure and UVR dose to the face. However, not all participants who reported good/excellent face photoprotection on the questionnaire recorded high levels of photoprotection in the daily diary. Correlations between the questionnaire and other practices and the clinical rating ranged from small to large in size. There was no correlation between the level of face photoprotection and self-reported avoidance of going outside. Our questionnaire was reliable and had good convergent validity with other indicators of photoprotection. This questionnaire could assist clinicians to detect low levels of adherence, and the methodology used to develop validated questionnaires for other photosensitive conditions.

Whole-Exome Sequencing Enables the Diagnosis of Variant-Type Xeroderma Pigmentosum.

BackgroundXeroderma pigmentosum (XP) is a rare autosomal, recessive, inherited disease. XP patients exhibit high sensitivity to sunlight and increased incidence of skin cancer. The different XP subtypes, which are caused by mutations of eight distinct genes, show some specific clinical manifestations. XP variant (XPV) is caused by mutations in the gene encoding DNA polymerase eta (POLH).Case PresentationWe report a family that included two XP patients whose parents were first cousins. The proband is a 36-year-old male who developed a large number of pigmented freckle-like lesions starting at 4 years of age; later, he displayed typical psoriasis manifestation, abnormal renal function and hyperglycaemia. He was suspected as suffering from dyschromatosis symmetrica hereditaria (DSH), but negative results were obtained in candidate gene analyses. Whole-exome sequencing was performed in four subjects, including the two patients and two controls, and a new pathogenic homozygous nonsense mutation (c.353dupA, p. Y118_V119delinsX) of the POLH gene, which was identified in all nine family members by Sanger sequencing, was detected in the patients.ConclusionA novel XPV pathogenic homozygous nonsense mutation in the POLH gene was identified. Our case proves that next-generation sequencing is an effective method for the rapid diagnosis and determination of XP genetic etiology.

127 Digital droplet PCR assays for the detection of leukemia mutations in a xeroderma pigmentosum patient with mixed phenotype acute leukemia

127 Digital droplet PCR assays for the detection of leukemia mutations in a xeroderma pigmentosum patient with mixed phenotype acute leukemia

High levels of oxidatively generated DNA damage 8,5′-cyclo-2′-deoxyadenosine accumulate in the brain tissues of xeroderma pigmentosum group A gene-knockout mice

Xeroderma pigmentosum (XP) is a genetic disorder associated with defects in nucleotide excision repair, a pathway that eliminates a wide variety of helix-distorting DNA lesions, including ultraviolet-induced pyrimidine dimers. In addition to skin diseases in sun-exposed areas, approximately 25% of XP patients develop progressive neurological disease, which has been hypothesized to be associated with the accumulation of an oxidatively generated type of DNA damage called purine 8,5′-cyclo-2′-deoxynucleoside (cyclopurine). However, that hypothesis has not been verified. In this study, we tested that hypothesis by using the XP group A gene-knockout (Xpa−/−) mouse model. To quantify cyclopurine lesions in this model, we previously established an enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody (CdA-1) that specifically recognizes 8,5′-cyclo-2′-deoxyadenosine (cyclo-dA). By optimizing conditions, we increased the ELISA sensitivity to a detection limit of ˜one cyclo-dA lesion/106 nucleosides. The improved ELISA revealed that cyclo-dA lesions accumulate with age in the brain tissues of Xpa−/− and of wild-type (wt) mice, but there were significantly more cyclo-dA lesions in Xpa−/− mice than in wt mice at 6, 24 and 29 months of age. These findings are consistent with the long-standing hypothesis that the age-dependent accumulation of endogenous cyclopurine lesions in the brain may be critical for XP neurological abnormalities.

Skin cancers in patients of skin phototype V or VI with xeroderma pigmentosum type C (XP-C): A retrospective study

Xeroderma pigmentosum (XP) is a rare genetic disease comprising 7 subgroups, A to G, all of which are associated with early onset of several forms of skin cancer. Our main objective was to determine the prevalence of skin cancers in a cohort of dark-skinned XP-C patients in Mayotte. A single-centre cohort consisting of all XP patients was followed in the island of Mayotte from December 2015 to May 2017 by dermatologists from the University Hospital of Saint-Denis (Reunion) during the course of dermatological missions. Eighteen patients of median age 12.9 years (7 female/11 male) belonging to 14 families were included. All had XP-C and carried the same mutation. Median age at clinical diagnosis of XP was 1.8 years. A total of 144 skin cancers (94 squamous cell carcinomas [SCC], 30 basal cell carcinomas [BCC], 14 melanomas, 5 sarcomas and 1 sarcomatoid carcinoma) were observed in 11 of the 18 patients (61%). Eleven patients (61%) had at least 1 SCC, 6 (33%) had at least 1 BCC, 6 (33%) had at least 1 melanoma, and 4 (22%) had at least 1 sarcoma. In all, 95.5% of the cancers occurred in light-exposed skin areas. Median age was 5.4 years for the initial cancer and 6.4 years for the second. SCCs and sarcomas occurred earlier than CBCs and melanomas (P<0.0001). All patients had mild to severe poikiloderma and presented photophobia, and 50% had pigmented palmoplantar lesions. One-third had oral mucosal involvement while 78% had ocular or palpebral lesions. Nail and hair involvement was recorded in 17% of patients. The median sun protection score (evaluated on a 7-item scale) was 6/7. The median score on the quality-of-life questionnaire (DLQI) was 4/30. Severity of poikiloderma was significantly correlated with the occurrence of skin cancers. Our cohort showed a high prevalence of skin cancer in XP-C patients of phototype V and VI exposed to UV radiation in a tropical region. SCCs were the most common tumours. The prevalence of melanoma was high, with major risk compared to controls of the same skin phototype. In addition, we found a high prevalence of sarcomas (5 patients). Initial cancers occurred early (5.4 years) compared to data from the literature, and SCCs and sarcomas occurred significantly sooner than melanomas and BCCs.

Xeroderma pigmentosum: overview of pharmacology and novel therapeutic strategies for neurological symptoms.

Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25-30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur. This appears to be secondary to dysfunctional NER but may contribute to the neurodegenerative process in these patients. The available pharmacological treatments in XP mostly target the dermal manifestations of the disease. In the present review, we outline how current understanding of the pathophysiology of XP could be used to develop novel therapies to counteract the neurological symptoms. Moreover, the coexistence of cancer and neurodegeneration present in XP led us to focus on possible new avenues targeting mitochondrial pathophysiology. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.

P.4.08 Metabolic syndrome, inflammation and oxidative stress as potential risk factors for affective disorders – a twin study

UVB radiation results in the formation of potentially mutagenic photoproducts in the DNA of epidermal skin cells. In vitro approaches have demonstrated that the nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small (∼30-nt-long), excised, damage-containing DNA oligonucleotides (sedDNAs). Though this process presumably takes place in human skin exposed to UVB radiation, sedDNAs have not previously been detected in human skin. Using surgically discarded human skin, we have optimized the detection of the sedDNA products of NER from small amounts of human epidermal tissue ex vivo within minutes of UVB exposure and after UVB doses that normally lead to minimal erythema. Moreover, sedDNA generation was inhibited by treatment of skin explants with spironolactone, which depletes the epidermis of the essential NER protein XPB to mimic the skin of xeroderma pigmentosum patients. Time course experiments revealed that a partially degraded form of the sedDNAs could be readily detected even 12 hours following UVB exposure, which indicates that these repair products are relatively stable in human skin epidermis. Together, these data suggest that sedDNA detection may be a useful assay for determining how genetic, environmental, and other factors influence NER activity in human skin epidermis and whether abnormal sedDNA processing contributes to photosensitive skin disorders.

Repair protein persistence at DNA lesions characterizes XPF defect with Cockayne syndrome features.

The structure-specific ERCC1-XPF endonuclease plays a key role in DNA damage excision by nucleotide excision repair (NER) and interstrand crosslink repair. Mutations in this complex can either cause xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome (XPCS-complex) or Fanconi anemia. However, most patients carry compound heterozygous mutations, which confounds the dissection of the phenotypic consequences for each of the identified XPF alleles. Here, we analyzed the functional impact of individual pathogenic XPF alleles on NER. We show that XP-causing mutations diminish XPF recruitment to DNA damage and only mildly affect global genome NER. In contrast, an XPCS-complex-specific mutation causes persistent recruitment of XPF and the upstream core NER machinery to DNA damage and severely impairs both global genome and transcription-coupled NER. Remarkably, persistence of NER factors at DNA damage appears to be a common feature of XPCS-complex cells, suggesting that this could be a determining factor contributing to the development of additional developmental and/or neurodegenerative features in XP patients.