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Muscle & Nerve Feb 2023Repair of genomic DNA is a fundamental housekeeping process that quietly maintains the health of our genomes. The consequences of a genetic defect affecting a component... (Review)
Review
Repair of genomic DNA is a fundamental housekeeping process that quietly maintains the health of our genomes. The consequences of a genetic defect affecting a component of this delicate mechanism are quite harmful, characterized by a cascade of premature aging that injures a variety of organs, including the nervous system. One part of the nervous system that is impaired in certain DNA repair disorders is the peripheral nerve. Chronic motor, sensory, and sensorimotor polyneuropathies have all been observed in affected individuals, with specific physiologies associated with different categories of DNA repair disorders. Cockayne syndrome has classically been linked to demyelinating polyneuropathies, whereas xeroderma pigmentosum has long been associated with axonal polyneuropathies. Three additional recessive DNA repair disorders are associated with neuropathies, including trichothiodystrophy, Werner syndrome, and ataxia-telangiectasia. Although plausible biological explanations exist for why the peripheral nerves are specifically vulnerable to impairments of DNA repair, specific mechanisms such as oxidative stress remain largely unexplored in this context, and bear further study. It is also unclear why different DNA repair disorders manifest with different types of neuropathy, and why neuropathy is not universally present in those diseases. Longitudinal physiological monitoring of these neuropathies with serial electrodiagnostic studies may provide valuable noninvasive outcome data in the context of future natural history studies, and thus the responses of these neuropathies may become sentinel outcome measures for future clinical trials of treatments currently in development such as adeno-associated virus gene replacement therapies.
Topics: Humans; Peripheral Nervous System Diseases; DNA Repair; Xeroderma Pigmentosum; Cockayne Syndrome; Polyneuropathies
PubMed: 36190439
DOI: 10.1002/mus.27721 -
Photochemistry and Photobiology 2015Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the United States, as well as premature skin aging. In... (Review)
Review
Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the United States, as well as premature skin aging. In particular, UVB radiation causes formation of specific DNA damage photoproducts between pyrimidine bases. These DNA damage photoproducts are repaired by a process called nucleotide excision repair, also known as UV-induced DNA repair. When left unrepaired, UVB-induced DNA damage leads to accumulation of mutations, predisposing people to carcinogenesis as well as to premature aging. Genetic loss of nucleotide excision repair leads to severe disorders, namely, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS), which are associated with predisposition to skin carcinogenesis at a young age as well as developmental and neurological conditions. Regulation of nucleotide excision repair is an attractive avenue to preventing or reversing these detrimental consequences of impaired nucleotide excision repair. Here, we review recent studies on molecular mechanisms regulating nucleotide excision repair by extracellular cues and intracellular signaling pathways, with a special focus on the molecular regulation of individual repair factors.
Topics: Aging; Carcinogenesis; Cockayne Syndrome; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Gene Expression Regulation; Humans; RNA Polymerase II; Signal Transduction; Skin Neoplasms; Trichothiodystrophy Syndromes; Ultraviolet Rays; Xeroderma Pigmentosum
PubMed: 25534312
DOI: 10.1111/php.12406 -
Central-European Journal of Immunology 2022Recurrent infections are important problems in syndromic patients. This study aimed to evaluate immunological abnormalities in patients who presented with recurrent...
INTRODUCTION
Recurrent infections are important problems in syndromic patients. This study aimed to evaluate immunological abnormalities in patients who presented with recurrent infections and were diagnosed with rare syndromes.
MATERIAL AND METHODS
This retrospective analysis included 14 patients with complaints of recurrent infections, all of whom were diagnosed with a rare syndrome.
RESULTS
The study group consisted of patients with Aicardi syndrome, Brugada syndrome, Phelan- McDermid syndrome, trichothiodystrophy, LEOPARD syndrome, Prader-Willi syndrome, Seckel syndrome, trisomy 18 (Edwards' syndrome), Wiedemann-Steiner syndrome, West syndrome, Williams syndrome, 47,XYY syndrome, 16p13 deletion syndrome, and 13q1.3 deletion syndrome. Seven patients (50%) were girls and seven (50%) were boys (mean age, 56.7 ±32.9 months; median [range] age: 45.5 [27-153] months). There were high rates of consanguinity (50%), cesarean section delivery (71%), and hospitalization in the intensive care unit (78.5%). No patients had a family history of immunodeficiency. On admission, all patients exhibited humoral and/or cellular immune system abnormalities. During the follow-up period, all T-cell abnormalities were improved after immunoglobulin replacement therapy (IGRT), while B-cell abnormalities persisted. These findings suggested that the patients predominantly had antibody deficiencies associated with mild T-cell abnormalities because of recurrent infections. The rates of infections and hospitalizations were significantly reduced after IGRT (p < 0.001); the rate of intensive care unit admission also significantly decreased (from 78.5% to 21.4%). Two of the three oxygen-dependent patients exhibited improvement therein. IGRT was discontinued in two patients with significant clinical improvement during follow-up.
CONCLUSIONS
An immunological evaluation should be considered in pediatric patients with rare syndromes and recurrent infections. IGRT may help to improve the prognoses of these patients.
PubMed: 36817395
DOI: 10.5114/ceji.2022.124080 -
Neuroscience Apr 2007Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair... (Review)
Review
Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked differences. NER is involved in protection against sunlight-induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes.
Topics: Brain Diseases, Metabolic, Inborn; Cockayne Syndrome; DNA Damage; DNA Repair; Heredodegenerative Disorders, Nervous System; Humans; Mutation; Phenotype; Skin Diseases, Genetic; Xeroderma Pigmentosum
PubMed: 17276014
DOI: 10.1016/j.neuroscience.2006.12.020 -
Genes and Environment : the Official... 2016Interstrand DNA crosslinks (ICLs) are the link between Watson-Crick strands of DNAs with the covalent bond and prevent separation of DNA strands. Since the ICL lesion... (Review)
Review
Interstrand DNA crosslinks (ICLs) are the link between Watson-Crick strands of DNAs with the covalent bond and prevent separation of DNA strands. Since the ICL lesion affects both strands of the DNA, the ICL repair is not simple. So far, nucleotide excision repair (NER), structure-specific endonucleases, translesion DNA synthesis (TLS), homologous recombination (HR), and factors responsible for Fanconi anemia (FA) are identified to be involved in ICL repair. Since the presence of ICL lesions causes severe defects in transcription and DNA replication, mutations in these DNA repair pathways give rise to a various hereditary disorders. NER plays an important role for the ICL recognition and removal in quiescent cells, and defects of NER causes congential progeria syndrome, such as xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. On the other hand, the ICL repair in S phase requires more complicated orchestration of multiple factors, including structure-specific endonucleases, and TLS, and HR. Disturbed this ICL repair orchestration in S phase causes genome instability resulting a cancer prone disease, Fanconi anemia. So far more than 30 factors in ICL repair have already identified. Recently, a new factor, UHRF1, was discovered as a sensor of ICLs. In addition to this, numbers of nucleases that are involved in the first incision, also called unhooking, of ICL lesions have also been identified. Here we summarize the recent studies of ICL associated disorders and repair mechanism, with emphasis in the first incision of ICLs.
PubMed: 27350828
DOI: 10.1186/s41021-016-0037-9 -
Cells Jun 2019The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and... (Review)
Review
The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Nucleolar malfunction has recently been described in the classical progeria of childhood, Hutchinson-Gilford syndrome (HGPS), which is characterized by severe signs of premature aging, including atherosclerosis, alopecia, and osteoporosis. A deregulated ribosomal biogenesis with enlarged nucleoli is not only characteristic for HGPS patients, but it is also found in the fibroblasts of "normal" aging individuals. Cockayne syndrome (CS) is also characterized by signs of premature aging, including the loss of subcutaneous fat, alopecia, and cataracts. It has been shown that all genes in which a mutation causes CS, are involved in rDNA transcription by RNA Pol I. A disturbed ribosomal biogenesis affects mitochondria and translates into ribosomes with a reduced translational fidelity that causes endoplasmic reticulum (ER) stress and apoptosis. Therefore, it is speculated that disease-causing disturbances in the process of ribosomal biogenesis may be more common than hitherto anticipated.
Topics: Aging, Premature; Cell Nucleolus; Child; Cockayne Syndrome; Endoplasmic Reticulum Stress; Humans; Mitochondria; Progeria; RNA Polymerase I; Ribosomes
PubMed: 31167386
DOI: 10.3390/cells8060534 -
The Journal of Investigative... Aug 2009Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome,... (Review)
Review
Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford syndrome, Fanconi anemia, and ataxia-telangiectasia, as well as xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome. Clinical symptoms of premature aging are skin atrophy with loss of cutaneous elasticity, dysfunction of cutaneous appendices, degeneration of the central nervous system and an increased susceptibility for malignant tumors. Genetic defects in the repair of DNA damage can lead to progeroid syndromes, and it is becoming increasingly evident that direct DNA damage and indirect damage by highly reactive oxygen species play central roles in aging. The clinical signs of progeroid syndromes and the molecular aspects of UV (ultraviolet radiation)-induced oxidative stress in aging are discussed.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 8-14; doi:10.1038/jidsymp.2009.6.
Topics: Ataxia Telangiectasia; Bloom Syndrome; Cockayne Syndrome; DNA Damage; DNA Repair; Fanconi Anemia; Female; Humans; Male; Models, Biological; Oxidative Stress; Progeria; Rothmund-Thomson Syndrome; Trichothiodystrophy Syndromes; Ultraviolet Rays; Werner Syndrome; Xeroderma Pigmentosum
PubMed: 19675546
DOI: 10.1038/jidsymp.2009.6 -
Seminars in Perinatology Feb 2013The ichthyoses encompass a variety of genetic disorders marked by abnormal epidermal differentiation. The neonatal period is critical for patients with ichthyosis... (Review)
Review
The ichthyoses encompass a variety of genetic disorders marked by abnormal epidermal differentiation. The neonatal period is critical for patients with ichthyosis because of the risk for significant associated morbidity and mortality, with the majority of complications arising as a result of impaired barrier function. This article reviews presentations of ichthyosis in the neonate, outlines risks and complications, and provides strategies for management.
Topics: Dehydration; Diagnosis, Differential; Directive Counseling; Ectropion; Female; Humans; Ichthyosis, Lamellar; Infant, Newborn; Male; Netherton Syndrome; Pain; Parents; Risk Factors; Sjogren-Larsson Syndrome; Staphylococcal Scalded Skin Syndrome; Stevens-Johnson Syndrome; Trichothiodystrophy Syndromes
PubMed: 23419760
DOI: 10.1053/j.semperi.2012.11.001 -
Oxidative Medicine and Cellular... 2019The continuous exposure of the human body's cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several... (Review)
Review
The continuous exposure of the human body's cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Deficiencies in the NER pathway underlie the development of several DNA repair diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Deficiencies in GG-NER and TC-NER render individuals to become prone to cancer and neurological disorders, respectively. Therefore, NER regulation is of interest in fine-tuning these risks. Distinct signaling cascades including the NFE2L2 (NRF2), AHR, PI3K/AKT1, MAPK, and CSNK2A1 pathways can modulate NER function. In addition, several chemical and biological compounds have proven success in regulating NER's activity. These modulators, particularly the positive ones, could therefore provide potential treatments for genetic DNA repair-based diseases. Negative modulators, nonetheless, can help sensitize cells to killing by genotoxic chemicals. In this review, we will summarize and discuss the major upstream signaling pathways and molecules that could modulate the NER's activity.
Topics: Animals; Cockayne Syndrome; DNA Damage; DNA Repair; Humans; Signal Transduction; Trichothiodystrophy Syndromes; Ultraviolet Rays; Xeroderma Pigmentosum
PubMed: 31485292
DOI: 10.1155/2019/4654206 -
Carcinogenesis Mar 2000DNA damage is implicated in cancer and aging, and several DNA repair mechanisms exist that safeguard the genome from these deleterious consequences. Nucleotide excision... (Review)
Review
DNA damage is implicated in cancer and aging, and several DNA repair mechanisms exist that safeguard the genome from these deleterious consequences. Nucleotide excision repair (NER) removes a wide diversity of lesions, the main of which include UV-induced lesions, bulky chemical adducts and some forms of oxidative damage. The NER process involves the action of at least 30 proteins in a 'cut-and-paste'-like mechanism. The consequences of a defect in one of the NER proteins are apparent from three rare recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and the photosensitive form of the brittle hair disorder trichothiodystrophy (TTD). Sun-sensitive skin is associated with skin cancer predisposition in the case of XP, but remarkably not in CS and TTD. Moreover, the spectrum of clinical symptoms differs considerably between the three syndromes. CS and TTD patients exhibit a spectrum of neurodevelopmental abnormalities and, in addition, TTD is associated with ichthyosis and brittle hair. These typical CS and TTD abnormalities are difficult to comprehend as a consequence of defective NER. This review briefly describes the biochemistry of the NER process, summarizes the clinical features of the NER disorders and speculates on the molecular basis underlying these pleitropic syndromes.
Topics: Cockayne Syndrome; DNA Damage; DNA Repair; Humans; Syndrome; Xeroderma Pigmentosum
PubMed: 10688865
DOI: 10.1093/carcin/21.3.453