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Trends in Genetics : TIG May 2001Trichothiodystrophy (TTD) is a rare genetic disorder characterized by a hair dysplasia and associated with numerous symptoms affecting mainly organs derived from the... (Review)
Review
Trichothiodystrophy (TTD) is a rare genetic disorder characterized by a hair dysplasia and associated with numerous symptoms affecting mainly organs derived from the neuroectoderm. About half of TTD patients exhibit photosensitivity because their nucleotide-excision repair pathway (NER) does not remove UV-induced DNA lesions efficiently. However, they do not present the skin cancer susceptibility expected from such an NER disorder. Their deficiencies result from phenotype-specific mutations in either XPB or XPD. These genes encode the helicase subunits of TFIIH, a DNA repair factor that is also required for transcription of class II genes. Thus, time- and tissue-specific impairments of transcription might explain the developmental and neurological symptoms of TTD. In a third group of photosensitive patients, TTD-A, no mutation has been identified, although TFIIH amount is reduced.
Topics: Abnormalities, Multiple; DNA Helicases; DNA Repair; DNA-Binding Proteins; Hair Diseases; Humans; Ichthyosis; Neurocutaneous Syndromes; Phenotype; Photosensitivity Disorders; Proteins; Transcription Factor TFIIH; Transcription Factors; Transcription Factors, TFII; Transcription, Genetic; Ultraviolet Rays; Xeroderma Pigmentosum Group D Protein
PubMed: 11335038
DOI: 10.1016/s0168-9525(01)02280-6 -
JAMA Dermatology Aug 2023
Topics: Humans; Trichothiodystrophy Syndromes; Hair; Sulfur; Hair Diseases
PubMed: 37342013
DOI: 10.1001/jamadermatol.2023.0913 -
American Family Physician Sep 2017Hair loss is often distressing and can have a significant effect on the patient's quality of life. Patients may present to their family physician first with diffuse or...
Hair loss is often distressing and can have a significant effect on the patient's quality of life. Patients may present to their family physician first with diffuse or patchy hair loss. Scarring alopecia is best evaluated by a dermatologist. Nonscarring alopecias can be readily diagnosed and treated in the family physician's office. Androgenetic alopecia can be diagnosed clinically and treated with minoxidil. Alopecia areata is diagnosed by typical patches of hair loss and is self-limited. Tinea capitis causes patches of alopecia that may be erythematous and scaly and must be treated systemically. Telogen effluvium is a nonscarring, noninflammatory alopecia of relatively sudden onset caused by physiologic or emotional stress. Once the precipitating cause is removed, the hair typically will regrow. Trichotillomania is an impulse-control disorder; treatment is aimed at controlling the underlying psychiatric condition. Trichorrhexis nodosa occurs when hairs break secondary to trauma and is often a result of hair styling or overuse of hair products. Anagen effluvium is the abnormal diffuse loss of hair during the growth phase caused by an event that impairs the mitotic activity of the hair follicle, most commonly chemotherapy. Physician support is especially important for patients in this situation.
Topics: Alopecia; Hair; Humans; Medical History Taking; Physical Examination; Tinea Capitis; Trichothiodystrophy Syndromes; Trichotillomania
PubMed: 28925637
DOI: No ID Found -
The New England Journal of Medicine Oct 2009
Review
Topics: Aging; Animals; Cockayne Syndrome; DNA Damage; DNA Repair; Disease Models, Animal; Genomic Instability; Humans; Mice; Neoplasms; Progeria; Trichothiodystrophy Syndromes; Xeroderma Pigmentosum
PubMed: 19812404
DOI: 10.1056/NEJMra0804615 -
Advances in Experimental Medicine and... 2010Although the term, "trichothiodystrophy" (TTD) refers to the hair anomalies in this group of patients, this is a heterogeneous, multisystem disease in which any or every... (Review)
Review
Although the term, "trichothiodystrophy" (TTD) refers to the hair anomalies in this group of patients, this is a heterogeneous, multisystem disease in which any or every organ in the body may be affected. Neuroectodermal derived tissues are particularly likely to be involved. This term was introduced by Price et alin 1980 to designate patients with sulfur-deficient brittle hair, which they recognized as a marker for this complex disease and designated it as a "neuroectodermal symptom complex". Patients with TTD have brittle hair and nails (associated with reduced content ofcysteine-rich matrix proteins), ichthyotic skin and physical and mental growth retardation. Ichthyosis is usually apparent at birth but much less so after the first few weeks of life. Other frequently associated features include ocular cataracts, infections and maternal complications related to pregnancy. Atrophy of subcutaneous fat may also be present. TTD occurs in a pattern of inheritance consistent with an autosomal recessive condition. The disease is extremely heterogeneous in severity and extent, with some patients showing no neurological deficiency. Others show severe, multisystem disease. Many patients die at a young age, most commonly due to infectious disease. TTD is part of a more broadly defined group of diseases identified as IBIDS (ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature). Photosensitive cases are also identified as PIBIDS (photosensitivity with IBIDS). Cases without manifest ichthyosis are also identified as PBIDS. These syndromes defy rigorous definition because of clinical variation between patients. The original two cases were described by Tay in oriental siblings, whose parents were first cousins; thus the disease is also known as Tay syndrome. The hairs in patients with TTD have a distinctive, diagnostically useful appearance on polarized light microscopy consisting of alternating light and dark bands known as the "tiger tail" anomaly. Diagnosis may be confirmed by sulfur content analysis ofhair shafts, which shows decreased sulfur and cysteine content. Approximately half of patients with TTD have photosensitivity, which correlates with a nudeotide excision repair (NER) defect. These patients are designated as having trichothiodystrophy-photosensitive (TTDP). Non-photosensitivepatients are designated as having trichothiodystrophy-nonphotosensitive (TTDN). Skin cancer is very rare in sun-sensitive TTD.
Topics: Animals; DNA Repair; DNA Repair-Deficiency Disorders; Female; Hair; Hair Diseases; Humans; Male; Nail Diseases; Pregnancy; Pregnancy Complications; Skin Neoplasms; Sulfur; Trichothiodystrophy Syndromes
PubMed: 20687499
DOI: 10.1007/978-1-4419-6448-9_10 -
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 -
DNA Repair Aug 2013DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead... (Review)
Review
DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within which they operate. For example, the human body is composed of non-dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye toward how these pathways may regulate the development of neurological disease.
Topics: Animals; DNA; DNA Damage; DNA Repair; Disease Models, Animal; Humans; Neurons; O(6)-Methylguanine-DNA Methyltransferase; Pyrimidine Dimers
PubMed: 23684800
DOI: 10.1016/j.dnarep.2013.04.015 -
Biochimie Nov 2003Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) are genetic disorders with very different clinical features, but all associated with... (Review)
Review
Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) are genetic disorders with very different clinical features, but all associated with defects in nucleotide excision repair. Defects in the XPA or XPC genes confer sensitivity to UV carcinogenesis in both humans and mice, but only XPA(-/-) mice have increased acute responses to UV exposure, whereas XPC(-/-) mice are normal in this respect. Both XPE and XPF proteins have functions separate from their role in NER, but the exact nature of these functions has not yet been established. The CSA and CSB genes responsible for CS are both components of complexes associated with RNA polymerase II and their role is thought to be in assisting polII in dealing with transcription blocks. XPB and XPD proteins are components of transcription factor TFIIH, which is involved in both basal and activated transcription. XPB is part of the core of TFIIH and has a central role in transcription, whereas XPD connects the core to the CAK subcomplex, and can tolerate many different mutations. Subtle differences in the effects of these different mutations on the many activities of TFIIH and on its stability determine the clinical outcomes, which can be XP, TTD, XP with CS, XP with TTD or COFS. Features of single and double mutant mice indicate that the neurological and ageing features associated with these disorders result from the defects in NER in association with the transcriptional deficiencies. Skin tumours in XP patients have mutations characteristic of UV-induction in the ras, p53 and ptch genes, showing that sunlight-induced mutations in these genes are important in carcinogenesis in XP patients.
Topics: Aging; Animals; Cockayne Syndrome; DNA Repair; Humans; Neoplasms; Nervous System Diseases; Xeroderma Pigmentosum
PubMed: 14726016
DOI: 10.1016/j.biochi.2003.09.010 -
Cell Mar 2017The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and...
The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
Topics: Aging; Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle Proteins; Cell Line; Cell Survival; Cell-Penetrating Peptides; Cellular Senescence; Doxorubicin; Female; Fibroblasts; Forkhead Transcription Factors; Humans; Inclusion Bodies; Kidney; Liver; Male; Mice; Trichothiodystrophy Syndromes; Tumor Suppressor Protein p53
PubMed: 28340339
DOI: 10.1016/j.cell.2017.02.031