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International Journal of Trichology 2018Trichothiodystrophy (TTD) is characterized by the common feature of sulfur-deficient brittle hair associated with a constellation of neuroectodermal symptoms. There is a...
Trichothiodystrophy (TTD) is characterized by the common feature of sulfur-deficient brittle hair associated with a constellation of neuroectodermal symptoms. There is a wide phenotypic variation in the severity; ranging from isolated hair defect to multiple neuroectodermal symptoms such as photosensitivity, ichthyosis, intellectual impairment, decreased fertility, and short stature. This case report describes TTD in two sisters with only hair fragility and no other associated feature. This case highlights the variable clinical presentation of TTD and the need for regular follow-up in such patients for an early detection of any neurological, physical, and sexual impairment.
PubMed: 30034195
DOI: 10.4103/ijt.ijt_63_17 -
Anais Brasileiros de Dermatologia 2018Trichothiodystrophy refers to a heterogeneous group of rare genetic diseases that affects neuroectodermal-derived tissues with multisystem involvement. The hallmark of...
Trichothiodystrophy refers to a heterogeneous group of rare genetic diseases that affects neuroectodermal-derived tissues with multisystem involvement. The hallmark of these syndromes is the deficiency of sulfur in hair matrix proteins, leading to short and brittle hair. Few cases of this rare disorder have been published. The authors report a case of trichothiodystrophy in a male infant with ichthyosis, photosensitivity, spastic paraparesis, short stature, and neurologic and psychomotor retardation. Diagnosis was based on clinical and microscopic features of hair samples.
Topics: Abnormalities, Multiple; Child, Preschool; Humans; Ichthyosis; Intellectual Disability; Male; Photosensitivity Disorders; Trichothiodystrophy Syndromes
PubMed: 29641717
DOI: 10.1590/abd1806-4841.20187727 -
PloS One 2018Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on...
OBJECTIVE
Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population.
METHODS
119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing.
RESULTS
Clinical and genetic features of hypomyelinating disorders were revealed. Nine different hypomyelinating disorders were identified in 119 patients: Pelizaeus-Merzbacher disease (94, 79%), Pelizaeus-Merzbacher-like disease (10, 8%), hypomyelination with atrophy of the basal ganglia and cerebellum (3, 3%), GM1 gangliosidosis (5, 4%), GM2 gangliosidosis (3, 3%), trichothiodystrophy (1, 1%), Pol III-related leukodystrophy (1, 1%), hypomyelinating leukodystrophy type 9 (1, 1%), and chromosome 18q deletion syndrome (1, 1%). Of the sample, 94% (112/119) of the patients were genetically diagnosed, including 111 with mutations distributing across 9 genes including PLP1, GJC2, TUBB4A, GLB1, HEXA, HEXB, ERCC2, POLR3A, and RARS and 1 with mosaic chromosomal change of 46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18. Eighteen novel mutations were discovered. Mutations in POLR3A and RARS were first identified in Chinese patients with Pol III-related leukodystrophy and hypomyelinating leukodystrophy, respectively.
SIGNIFICANCE
This is the first report on clinical and genetic features of hypomyelinating disorders with a large sample of patients in Chinese population, identifying 18 novel mutations especially mutations in POLR3A and RARS in Chinese patients, expanding clinical and genetic spectrums of hypomyelinating disorders.
Topics: China; Chromosome Banding; Female; Genetic Heterogeneity; Hereditary Central Nervous System Demyelinating Diseases; Humans; Infant; Infant, Newborn; Karyotyping; Magnetic Resonance Imaging; Male
PubMed: 29451896
DOI: 10.1371/journal.pone.0188869 -
Journal of Molecular and Genetic... 2018The S100B protein is an intra- and extracellular signaling protein that plays a role in a multitude of cellular processes and abnormal S100B is associated with various...
The S100B protein is an intra- and extracellular signaling protein that plays a role in a multitude of cellular processes and abnormal S100B is associated with various neurological diseases and cancers. S100B recognizes and binds effector proteins in a calcium-dependent manner. S100B has been shown to interact with the actin capping protein CapZ, protein kinase C, Hdm2 and 4, RAGE receptor, and p, among others. These protein partners interact with a common area on the S100B protein surface, validating the method of using the consensus sequence for S100B target search. In addition, each S100B target protein distinguishes itself by additional contacts with S100B. This perspective suggests that the combination of sequence homology search and structural analysis promises to identify newer S100B-binding partners beyond the use of the consensus sequence alone as the given example in the XPB subunit of the TFIIH general transcription factor. XPB is a helicase required for both transcription and DNA repair. Inherited xpb mutations are associated with human disease Xeroderma Pigmentasum, Cockayne syndrome, and trichothiodystrophy. S100B protein is likely associated with much more biological pathways and processes. We believe that S100B will attract more and more attentions in the scientific community and S100B related studies will have important implications in human health and medicine.
PubMed: 30854023
DOI: 10.4172/1747-0862.1000366 -
Nature Nov 2017DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions, which are sensed by distinct pathways to recruit repair factors...
DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions, which are sensed by distinct pathways to recruit repair factors specific to the damage type. Although biochemical mechanisms for repairing several forms of genomic insults are well understood, the upstream signalling pathways that trigger repair are established for only certain types of damage, such as double-stranded breaks and interstrand crosslinks. Understanding the upstream signalling events that mediate recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment and because environmental chemicals may trigger DNA alkylation. Here we demonstrate that human cells have a previously unrecognized signalling mechanism for sensing damage induced by alkylation. We find that the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents. These foci associate with alkylated nucleotides, and coincide spatially with elongating RNA polymerase II and splicing components. Proper recruitment of the repair complex requires recognition of K63-linked polyubiquitin by the CUE (coupling of ubiquitin conjugation to ER degradation) domain of the subunit ASCC2. Loss of this subunit impedes alkylation adduct repair kinetics and increases sensitivity to alkylating agents, but not other forms of DNA damage. We identify RING finger protein 113A (RNF113A) as the E3 ligase responsible for upstream ubiquitin signalling in the ASCC pathway. Cells from patients with X-linked trichothiodystrophy, which harbour a mutation in RNF113A, are defective in ASCC foci formation and are hypersensitive to alkylating agents. Together, our work reveals a previously unrecognized ubiquitin-dependent pathway induced specifically to repair alkylation damage, shedding light on the molecular mechanism of X-linked trichothiodystrophy.
Topics: AlkB Enzymes; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Alkylating Agents; Alkylation; Amino Acid Sequence; DNA Adducts; DNA Helicases; DNA Repair; DNA-Binding Proteins; Endoplasmic Reticulum; Genes, X-Linked; Humans; Kinetics; Models, Molecular; Multiprotein Complexes; Nuclear Proteins; Polyubiquitin; RNA Polymerase II; RNA Splicing; Signal Transduction; Trichothiodystrophy Syndromes; Ubiquitin; Ubiquitination
PubMed: 29144457
DOI: 10.1038/nature24484 -
Nucleic Acids Research Oct 2017The general transcription factor IIH (TFIIH) is a multi-protein complex and its 10 subunits are engaged in an intricate protein-protein interaction network critical for...
The general transcription factor IIH (TFIIH) is a multi-protein complex and its 10 subunits are engaged in an intricate protein-protein interaction network critical for the regulation of its transcription and DNA repair activities that are so far little understood on a molecular level. In this study, we focused on the p44 and the p34 subunits, which are central for the structural integrity of core-TFIIH. We solved crystal structures of a complex formed by the p34 N-terminal vWA and p44 C-terminal zinc binding domains from Chaetomium thermophilum and from Homo sapiens. Intriguingly, our functional analyses clearly revealed the presence of a second interface located in the C-terminal zinc binding region of p34, which can rescue a disrupted interaction between the p34 vWA and the p44 RING domain. In addition, we demonstrate that the C-terminal zinc binding domain of p34 assumes a central role with respect to the stability and function of TFIIH. Our data reveal a redundant interaction network within core-TFIIH, which may serve to minimize the susceptibility to mutational impairment. This provides first insights why so far no mutations in the p34 or p44 TFIIH-core subunits have been identified that would lead to the hallmark nucleotide excision repair syndromes xeroderma pigmentosum or trichothiodystrophy.
Topics: Chaetomium; Fungal Proteins; Humans; Models, Molecular; Mutation; Protein Interaction Domains and Motifs; Protein Subunits; Transcription Factor TFIIH
PubMed: 28977422
DOI: 10.1093/nar/gkx743 -
Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue.Human Molecular Genetics Dec 2017The rare recessive developmental disorder Trichothiodystrophy (TTD) is characterized by brittle hair and nails. Patients also present a variable set of poorly explained...
The rare recessive developmental disorder Trichothiodystrophy (TTD) is characterized by brittle hair and nails. Patients also present a variable set of poorly explained additional clinical features, including ichthyosis, impaired intelligence, developmental delay and anemia. About half of TTD patients are photosensitive due to inherited defects in the DNA repair and transcription factor II H (TFIIH). The pathophysiological contributions of unrepaired DNA lesions and impaired transcription have not been dissected yet. Here, we functionally characterize the consequence of a homozygous missense mutation in the general transcription factor II E, subunit 2 (GTF2E2/TFIIEβ) of two unrelated non-photosensitive TTD (NPS-TTD) families. We demonstrate that mutant TFIIEβ strongly reduces the total amount of the entire TFIIE complex, with a remarkable temperature-sensitive transcription defect, which strikingly correlates with the phenotypic aggravation of key clinical symptoms after episodes of high fever. We performed induced pluripotent stem (iPS) cell reprogramming of patient fibroblasts followed by in vitro erythroid differentiation to translate the intriguing molecular defect to phenotypic expression in relevant tissue, to disclose the molecular basis for some specific TTD features. We observed a clear hematopoietic defect during late-stage differentiation associated with hemoglobin subunit imbalance. These new findings of a DNA repair-independent transcription defect and tissue-specific malfunctioning provide novel mechanistic insight into the etiology of TTD.
Topics: Cell Differentiation; Cellular Reprogramming; DNA Helicases; DNA Repair; Female; Humans; Induced Pluripotent Stem Cells; Male; Mutation; Mutation, Missense; Organ Specificity; Pedigree; Transcription Factors, TFII; Transcription, Genetic; Trichothiodystrophy Syndromes
PubMed: 28973399
DOI: 10.1093/hmg/ddx351 -
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 -
Nature Sep 2017Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene...
Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 Å resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Cryoelectron Microscopy; Humans; Models, Molecular; Mutation; Protein Subunits; RNA Polymerase II; Transcription Factor TFIIH; Transcription Initiation, Genetic
PubMed: 28902838
DOI: 10.1038/nature23903 -
Indian Journal of Dermatology,... 2017
Topics: Cumulative Trauma Disorders; Hair Diseases; Humans; Trichothiodystrophy Syndromes
PubMed: 28656909
DOI: 10.4103/ijdvl.IJDVL_45_16