Form Of Xeroderma Pigmentosum Research Articles

A novel frameshift mutation in the XPC gene in a Moroccan patient: a case report

BackgroundXeroderma pigmentosum is an autosomal recessive inherited disease. The diagnosis is essentially based on clinical findings and the family history. This genodermatosis is genetically heterogeneous; to date, nine genes have been associated to this disorder. Based on the result of many studies, xeroderma pigmentosum complementation group C is the most common form of xeroderma pigmentosum. A founder mutation in the XPC gene was reported in the Maghreb region of northern Africa. According to these findings, the Department of Medical Genetics in Rabat offers molecular diagnosis by screening for the recurrent mutation c.1643_1644delTG which represents 74% of all the probands with xeroderma pigmentosum.Case presentationWe describe the case of a 21-year-old Moroccan son of consanguineous parents diagnosed with xeroderma pigmentosum on the basis of sun-exposed skin abnormalities and bilateral ocular involvement.A molecular study led to the identification of a new frameshift insertion of four nucleotides in exon 9.ConclusionsTo the best of our knowledge, this mutation has not been described. The sequencing of the ninth exon should be proposed as first line molecular analysis for all Moroccan patients with xeroderma pigmentosum.

Mutations in Cockayne Syndrome-Associated Genes (Csa and Csb) Predispose to Cisplatin-Induced Hearing Loss in Mice.

Cisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly understood, as are the specific DNA repair pathways that protect these cells. Nucleotide excision repair (NER) is a conserved and versatile DNA repair pathway for many DNA-distorting lesions, including cisplatin-DNA adducts. Progressive sensorineural hearing loss is observed in a subset of NER-associated DNA repair disorders including Cockayne syndrome and some forms of xeroderma pigmentosum. We investigated whether either of the two overlapping branches that encompass NER, transcription-coupled repair or global genome repair, which are implicated in Cockayne syndrome and xeroderma pigmentosum group C, respectively, modulates cisplatin-induced hearing loss and cell death in the organ of Corti, the auditory sensory epithelium of mammals. We report that cochlear hair cells and supporting cells in transcription-coupled repair-deficient Cockayne syndrome group A (Csa(-/-)) and group B (Csb(-/-)) mice are hypersensitive to cisplatin, in contrast to global genome repair-deficient Xpc(-/-) mice, both in vitro and in vivo We show that sensory hair cells in Csa(-/-) and Csb(-/-) mice fail to remove cisplatin-DNA adducts efficiently in vitro; and unlike Xpc(-/-) mice, Csa(-/-) and Csb(-/-) mice lose hearing and manifest outer hair cell degeneration after systemic cisplatin treatment. Our results demonstrate that Csa and Csb deficiencies predispose to cisplatin-induced hearing loss and hair/supporting cell damage in the mammalian organ of Corti, and emphasize the importance of transcription-coupled DNA repair in the protection against cisplatin ototoxicity. The utility of cisplatin in chemotherapy remains limited due to serious side effects, including sensorineural hearing loss. We show that mouse models of Cockayne syndrome, a progeroid disorder resulting from a defect in the transcription-coupled DNA repair (TCR) branch of nucleotide excision repair, are hypersensitive to cisplatin-induced hearing loss and sensory hair cell death in the organ of Corti, the mammalian auditory sensory epithelium. Our work indicates that Csa and Csb, two genes involved in TCR, are preferentially required to protect against cisplatin ototoxicity, relative to global genome repair-specific elements of nucleotide excision repair, and suggests that TCR is a major force maintaining DNA integrity in the cochlea. The Cockayne syndrome mice thus represent a model for testing the contribution of DNA repair mechanisms to cisplatin ototoxicity.

Structure of monoubiquitinated PCNA

Ubiquitination of proliferating cell nuclear antigen (PCNA) to ub-PCNA is essential for DNA replication across bulky template lesions caused by UV radiation and alkylating agents, as ub-PCNA orchestrates the recruitment and switching of translesion synthesis (TLS) polymerases with replication polymerases. This allows replication to proceed, leaving the DNA to be repaired subsequently. Defects in a TLS polymerase, Pol η, lead to a form of Xeroderma pigmentosum, a disease characterized by severe skin sensitivity to sunlight damage and an increased incidence of skin cancer. Structurally, however, information on how ub-PCNA orchestrates the switching of these two classes of polymerases is lacking. We have solved the structure of ub-PCNA and demonstrate that the ubiquitin molecules in ub-PCNA are radially extended away from the PCNA without structural contact aside from the isopeptide bond linkage. This unique orientation provides an open platform for the recruitment of TLS polymerases through ubiquitin-interacting domains. However, the ubiquitin moieties, to the side of the equatorial PCNA plane, can place spatial constraints on the conformational flexibility of proteins bound to ub-PCNA. We show that ub-PCNA is impaired in its ability to support the coordinated actions of Fen1 and Pol δ in assays mimicking Okazaki fragment processing. This provides evidence for the novel concept that ub-PCNA may modulate additional DNA transactions other than TLS polymerase recruitment and switching.

Xeroderma pigmentosum group F protein binds to Eg5 and is required for proper mitosis: implications for XP‐F and XFE

The xeroderma pigmentosum group F-cross-complementing rodent repair deficiency group 1 (XPF-ERCC1) complex is a structure-specific endonuclease involved in nucleotide excision repair (NER) and interstrand cross-link (ICL) repair. Patients with XPF mutations may suffer from two forms of xeroderma pigmentosum (XP): XP-F patients show mild photosensitivity and proneness to skin cancer but rarely show any neurological abnormalities, whereas XFE patients display symptoms of severe XP symptoms, growth retardation and accelerated aging. Xpf knockout mice display accelerated aging and die before weaning. These results suggest that the XPF-ERCC1 complex has additional functions besides NER and ICL repair and is essential for development and growth. In this study, we show a partial colocalization of XPF with mitotic spindles and Eg5. XPF knockdown in cells led to an increase in the frequency of abnormal nuclear morphology and mitosis. Similarly, the frequency of abnormal nuclei and mitosis was increased in XP-F and XFE cells. In addition, we showed that Eg5 enhances the action of XPF-ERCC1 nuclease activity. Taken together, these results suggest that the interaction between XPF and Eg5 plays a role in mitosis and DNA repair and offer new insights into the pathogenesis of XP-F and XFE.

Xeroderma pigmentosum compliqué d’une tumeur intracérébrale : à propos d’un cas

Patients with the genetic disease xeroderma pigmentosum (XP) lack the ability to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from ultraviolet (UV) radiation. We report a case of a patient presenting a cutaneous form of XP. She presented acute paralysis of the third cranial nerve with cutaneous anesthesia. Nuclear magnetic resonance imaging revealed an intracranial tumor. She underwent surgery with incomplete tumor resection; anatomopathological study showed a schwannoma. Complementary radiosurgery was performed. The association between XP and neurological cancer is rare but not impossible. A priori, it would be assumed that the major medical outcome of hereditary deficiencies in DNA repair processes would be an increased risk of cancer. Indeed, there is an increased risk of cancer in several known DNA repair deficiencies including XP.

The XPG story

I provide a personal account of the discovery, cloning and functional analyses of the human XPG gene. Mutations in this gene can give rise to the group G form of xeroderma pigmentosum (XP) and, in some cases, to severe early onset Cockayne syndrome (CS). The XPG protein has well established catalytic and structural roles in nucleotide excision repair (NER) and it acts as a cofactor for a DNA glycosylase that removes oxidised pyrimidines from DNA. XPG may also be involved in transcription-coupled repair of this kind of damage, in transcription by RNA polymerase II, and perhaps in other processes too. Our current knowledge of this important protein is largely based on some excellent, highly focussed science. But good luck, serendipity and scientific scandal have also made major contributions to this unfinished story.

Gene therapy and beyond

Elisabeth Tournier-Lasserve is professor of genetics at Faculte de Medecine Lariboisiere-St Louis, and director of INSERM Unit EPI99-21, where she researches the genetics of vascular disorders and the genetics of autoimmune disorders. Molecular genetics' impressive progress over the past 20 years was made possible by the discovery of DNA's structure, the ability to have direct access to genetics thanks to the development of cloning, sequencing, and PCR amplification as well as the ability to map and identify disease genes because of the development of microsatellite polymorphic markers and yeast artificial chromosomes. Medical genetics, formerly a paediatric discipline, now pervades all medical specialties. The genes involved in several hundreds of monogenic disorders have been localised or identified. This discovery allows a better understanding of the underlying mechanisms, and it ushers in new developments in biology. Clinical observations such as anticipation phenomena, seen in several neurological diseases, Steinert's disease, Huntington's chorea, and some ataxias, have been correlated to abnormal expansion of nucleotide triplets. The mystery of clinical phenotypical differences in Prader-Willi and Angelman's syndrome–depending on whether the condition is transmitted by the father or by the mother–has been elucidated. And the concept of parental imprinting has been extended to many other disorders. New nosological frameworks have appeared. Identification of the role of ion channels in many diseases– generally sharing paroxysmal characteristics (eg, long QT syndrome, hyper- or hypokalaemic paralysis, hemiplegic migraine)–led to the concept of ‘channelopathy’, a steadily expanding field. The 1990s witnessed the expansion of the field of DNA-repair disorders, coinciding with the identification of the genes of ataxia telangiectasia, Bloom's syndrome, and various forms of xeroderma pigmentosum. This to and fro between clinical medicine and molecular biology is not limited to the definition of nosological frameworks. Molecular genetics' applications to the diagnosis of hereditary diseases are plentiful, both in prenatal diagnosis of severe early-onset disorders and in presymptomatic ("positive”) diagnosis of adult-onset hereditary diseases. Molecular tools–valuable for genetic counselling–can also help in the positive diagnosis of disease in adults, and also help to identify the clinical and prognostic variants of a disease, according to the molecular abnormality involved. Advances in predictive medicine are not devoid of ethical repercussions. Care of patients, couples, or family members is multidisciplinary, and involves geneticists and other clinicians, and in some cases psychologists. The momentum of this particular aspect of care and the speed at which findings evolve requires the setting up of centres that are specialised in some groups of diseases. Progress during the past 20 years and the fascinating aspects of new research domains should not lead us to forget at least two challenges for the next 10 years: the identification of genes involved in multifactorial polygenic diseases, and the development of therapies. Identification of genetic variants in the determination of cardiovascular diseases, of autoimmune diseases, and of asthma remains a challenge because the methods used lack power, because of the heterogeneity of these disorders, and because of the very large number of patients who have to be analysed. International collaborations and close commitment of many clinicians should allow recruitment of the very large cohorts needed for this unavoidable step during the next 5 years. However, financial means must be made available to the teams. The greatest challenge concerns the development of therapy. Between 1980 and 2000, genes of many disorders have been identified and diagnostic tests developed. However, patients expect effective treatments. Hopes for gene transfer have led to nearly 400 gene-therapy trials (eg, for cystic fibrosis, immune deficiencies, or cardiovascular diseases). Studies have improved the vectors used for transfer, g- but generally, effects do not yet meet expectations. In most cases, either the ? correction was not enough to reverse clinical abnormalities, or was limited by rapid extinction of the transgene expression. However, the clinically spectacular effects recently observed in patients with severe lower limb arterial disease after intramuscular administration of a plasmid containing the VEGF gene clearly show that this avenue must be pursued. Perhaps the method will be applied successfully outside the domain of monogenic disorders. The therapeutic approach to these disorders may soon no longer be restricted to gene therapy but may harness conventional pharmacology, as was recently suggested in Friedreich's ataxia. Formerly limited to the diagnosis of rare diseases by means of dysmorphic features, genetics of the second millennium now invades all specialties. This has allowed unprecedented accumulation of knowledge about diseases. Pursuing these interactions, and their extension to pharmaceutical industry and bio-technological firms, is undoubtedly the ground from which treatments shall rise.

Ultraviolet Hypermutablity of a Shuttle Vector Propagated in Xeroderma Pigmentosum Variant Cells

Patients with the variant form of xeroderma pigmentosum (XP) have clinical XP including a high frequency of skin cancer but, in contrast to the other forms of XP, have normal post-ultraviolet (UV) DNA excision repair and nearly normal post-UV survival. However, like excision repair-deficient XP cells, the XP variant cells are UV hypermutable. We used a UV-treated plasmid shuttle vector, pZ189, to examine the DNA repair defect in lymphoblastoid cells from an XP variant patient, XPPHBE, and a normal control. Plasmid repair, mutagenesis, and replication occur within transfected cells in a process dependent on the cells' repair capacity. With the XP variant cells post-UV, plasmid survival was normal with but there was an abnormally increased post-UV plasmid mutation frequency. Sequence analysis of the mutated plasmids revealed an increased frequency of plasmids with single base substitution mutations with the XP variant cells. As in earlier studies with UV mutagenesis, there was a predominance of G:C-->A:T base substitution mutations with plasmids recovered from both cell lines. The frequency of G:C-->C:G transversions was significantly higher with plasmids recovered from the XP variant cells than from normal cells. The location of mutations in the marker gene was non-random with different mutagenic hotspots found in plasmids recovered from the XP variant cells and from the normal cells. This study suggests that plasmid UV hypermutability in the presence of normal UV survival may be related to the increased UV skin cancer susceptibility of XP variant patients.

Gamma-Ray-Enhanced Reactivation of Irradiated Adenovirus in Xeroderma Pigmentosum and Cockayne Syndrome Fibroblasts

A gamma-ray-enhanced reactivation (gamma RER) of uv-irradiated as well as of gamma-irradiated human adenovirus type 2 (Ad 2) was detected following infection of normal, Xeroderma pigmentosum (XP), and Cockayne syndrome (CS) fibroblasts that had been preirradiated with gamma rays. Gamma-irradiated or nonirradiated fibroblasts were infected with either nonirradiated or irradiated Ad 2, and 48 hr after infection cells were examined for the presence of viral structural antigens (Vag) using immunofluorescent staining. Results obtained using seven different normal fibroblast strains showed that irradiation of host monolayers with 1 krad immediately prior to infection resulted in a gamma RER factor +/- SE of 4.5 +/- 1.6 for uv-irradiated virus and 4.3 +/- 1.3 for gamma-irradiated virus. CS fibroblasts, as well as excision repair-deficient XP fibroblasts from complementation groups A and D, were all found to be capable of expressing gamma RER of irradiated Ad 2. XP variant cells expressed lower levels of gamma RER compared to most normal strains, suggesting a possible role for cellular postreplication repair in the mechanism responsible for ER in human cells. An excision-deficient XP fibroblast strain belonging to complementation group A, but derived from a patient afflicted with the severe De Sanctis-Cacchione form of XP, although proficient in gamma RER of gamma-irradiated Ad 2, yielded barely detectable levels of gamma RER for uv-irradiated Ad 2.

DNA Repair Processes Protect Human Beings from Premature Solar Skin Damage: Evidence from Studies on Xeroderma Pigmentosum

The repair of DNA damage by ultraviolet light is defective in the hereditary disease xeroderma pigmentosum. A deoxyribonucleotide excision-proficient form and several excision-deficient forms of xeroderma pigmentosum have been identified. Premature solar skin damage develops in all xeroderma pigmentosum patients. Some patients also have neurological abnormalities caused by premature death of nerve cells. This abnormal aging of the central nervous system and of sun-exposed skin appears to be the result of the abnormal DNA repair processes. Clinical, biological, and physicochemical studies on DNA-repair-dependent processes and on the DNA repair defects in xeroderma pigmentosum are elucidating the mechanisms by which such abnormal aging is prevented in normal human beings.

Xeroderma Pigmentosum Variants: Influence of Temperature on Dna Repair

Three forms of xeroderma pigmentosum (XP) are currently known: the common form, the de Sanctis-Cacchione syndrome with neurologic involvement, and the XP variant. The first two forms are associated with a reduced capacity of cells to perform excision repair of ultraviolet (UV) damage to DNA. The XP variant clinically resembles the other forms of XP, but cells from these patients have a normal response to UV light when measured at 37°C. Fibroblasts from a patient with the variant type of XP were tested to see if they were still similar to normal cells a reduced temperature. The XP variant was found to be indistinguishable from normal cells, and both carried out similar amounts of DNA repair. This form of XP, then, should be regarded as quite distinct from the other two major forms and probably has an etiology that does not involve a defect in DNA repair.

Differentiation of two forms of xeroderma pigmentosum.

Differentiation of two forms of xeroderma pigmentosum.