-
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 -
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 -
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 -
Dermatology and Therapy Sep 2019Hair loss in early childhood represents a broad differential diagnosis which can be a diagnostic and therapeutic challenge for a physician. It is important to consider... (Review)
Review
Hair loss in early childhood represents a broad differential diagnosis which can be a diagnostic and therapeutic challenge for a physician. It is important to consider the diagnosis of a genetic hair disorder. Genetic hair disorders are a large group of inherited disorders, many of which are rare. Genetic hair abnormalities in children can be an isolated phenomenon or part of genetic syndromes. Hair changes may be a significant finding or even the initial presentation of a syndrome giving a clue to the diagnosis, such as Netherton syndrome and trichothiodystrophy. Detailed history including family history and physical examination of hair and other ectodermal structures such as nails, sweat glands, and sebaceous glands with the use of dermoscopic devices and biopsy all provide important clues to establish the correct diagnosis. Understanding the pathophysiology of genetic hair defects will allow for better comprehension of their treatment and prognosis. For example, in patients with an isolated hair defect, the main problem is aesthetic. In contrast, when the hair defect is associated with a syndrome, the prognosis will depend mainly on the associated condition. Treatment of many genetic hair disorders is focused on treating the primary cause and minimizing trauma to the hair.
PubMed: 31332722
DOI: 10.1007/s13555-019-0313-2 -
Open Biology Oct 2019Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental... (Review)
Review
Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human disorders caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated ageing. All three syndromes include developmental abnormalities, indicating an important role for optimal transcription and for NER in protecting against spontaneous DNA damage during embryonic development. Here, we review the current knowledge on genes that function in NER that also affect embryonic development, in particular the development of a fully functional nervous system.
Topics: Animals; Cockayne Syndrome; DNA Repair; DNA Repair Enzymes; Embryonic Development; Humans; Phenotype
PubMed: 31662099
DOI: 10.1098/rsob.190166 -
DNA Repair Dec 2023The heterodecameric transcription factor IIH (TFIIH) functions in multiple cellular processes, foremost in nucleotide excision repair (NER) and transcription initiation... (Review)
Review
The heterodecameric transcription factor IIH (TFIIH) functions in multiple cellular processes, foremost in nucleotide excision repair (NER) and transcription initiation by RNA polymerase II. TFIIH is essential for life and hereditary mutations in TFIIH cause the devastating human syndromes xeroderma pigmentosum, Cockayne syndrome or trichothiodystrophy, or combinations of these. In NER, TFIIH binds to DNA after DNA damage is detected and, using its translocase and helicase subunits XPB and XPD, opens up the DNA and checks for the presence of DNA damage. This central activity leads to dual incision and removal of the DNA strand containing the damage, after which the resulting DNA gap is restored. In this review, we discuss new structural and mechanistic insights into the central function of TFIIH in NER. Moreover, we provide an elaborate overview of all currently known patients and diseases associated with inherited TFIIH mutations and describe how our understanding of TFIIH function in NER and transcription can explain the different disease features caused by TFIIH deficiency.
Topics: Humans; Transcription Factor TFIIH; Xeroderma Pigmentosum Group D Protein; DNA Repair; Xeroderma Pigmentosum; DNA
PubMed: 37977600
DOI: 10.1016/j.dnarep.2023.103568 -
EMBO Molecular Medicine Nov 2023The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation,...
The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady-state mutant protein levels. However, to date, no such link to instability of gene-expression factors for TTD-associated mutations in MPLKIP/TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry-based interaction proteomics, we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP-deficient primary fibroblasts have reduced steady-state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue.
Topics: Humans; Adaptor Proteins, Signal Transducing; Consanguinity; Mutation; Phenotype; RNA Splicing; Trichothiodystrophy Syndromes
PubMed: 37800682
DOI: 10.15252/emmm.202317973 -
Mutation Research 2013Helicases have important roles in nucleic acid metabolism, and their prominence is marked by the discovery of genetic disorders arising from disease-causing mutations.... (Review)
Review
Helicases have important roles in nucleic acid metabolism, and their prominence is marked by the discovery of genetic disorders arising from disease-causing mutations. Missense mutations can yield unique insight to molecular functions and basis for disease pathology. XPB or XPD missense mutations lead to Xeroderma pigmentosum, Cockayne's syndrome, Trichothiodystrophy, or COFS syndrome, suggesting that DNA repair and transcription defects are responsible for clinical heterogeneity. Complex phenotypes are also observed for RECQL4 helicase mutations responsible for Rothmund-Thomson syndrome, Baller-Gerold syndrome, or RAPADILINO. Bloom's syndrome causing missense mutations are found in the conserved helicase and RecQ C-terminal domain of BLM that interfere with helicase function. Although rare, patient-derived missense mutations in the exonuclease or helicase domain of Werner syndrome protein exist. Characterization of WRN separation-of-function mutants may provide insight to catalytic requirements for suppression of phenotypes associated with the premature aging disorder. Characterized FANCJ missense mutations associated with breast cancer or Fanconi anemia interfere with FANCJ helicase activity required for DNA repair and the replication stress response. For example, a FA patient-derived mutation in the FANCJ Iron-Sulfur domain was shown to uncouple its ATPase and translocase activity from DNA unwinding. Mutations in DDX11 (ChlR1) are responsible for Warsaw Breakage syndrome, a recently discovered autosomal recessive cohesinopathy. Ongoing and future studies will address clinically relevant helicase mutations and polymorphisms, including those that interfere with key protein interactions or exert dominant negative phenotypes (e.g., certain mutant alleles of Twinkle mitochondrial DNA helicase). Chemical rescue may be an approach to restore helicase activity in loss-of-function helicase disorders. Genetic and biochemical analyses of disease-causing missense mutations in human helicase disorders have led to new insights to the molecular defects underlying aberrant cellular and clinical phenotypes.
Topics: Bloom Syndrome; Cockayne Syndrome; DNA Helicases; Fanconi Anemia; Humans; Mutation, Missense; Xeroderma Pigmentosum
PubMed: 23276657
DOI: 10.1016/j.mrrev.2012.12.004