Assuntos
Neutropenia/diagnóstico , Neutropenia/etiologia , Síndrome de Rothmund-Thomson/diagnóstico , Síndrome de Rothmund-Thomson/etiologia , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/etiologia , Alelos , Diagnóstico Diferencial , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Mutação , FenótipoRESUMO
The RecQ family of helicases has been shown to play an important role in maintaining genomic stability. In humans, this family has five members and mutations in three of these helicases, BLM, WRN and RECQL4, are associated with disease. Alterations in RECQL4 are associated with three diseases, Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILINO syndrome. One of the more common mutations found in RECQL4 is the RAPADILINO mutation, c.1390+2delT which is a splice-site mutation leading to an in-frame skipping of exon 7 resulting in 44 amino acids being deleted from the protein (p.Ala420-Ala463del). In order to characterize the RAPADILINO RECQL4 mutant protein, it was expressed in bacteria and purified using an established protocol. Strand annealing, helicase, and ATPase assays were conducted to characterize the protein's activities relative to WT RECQL4. Here we show that strand annealing activity in the absence of ATP is unchanged from that of WT RECQL4. However, the RAPADILINO protein variant lacks helicase and ssDNA-stimulated ATPase activity. These observations help explain the underlying molecular etiology of the disease and our findings provide insight into the genotype and phenotype association among RECQL4 syndromes.
Assuntos
Nanismo , Comunicação Interatrial , Deformidades Congênitas dos Membros , Mutação/genética , Sítios de Splice de RNA/genética , RecQ Helicases/genética , Síndrome de Rothmund-Thomson , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Canal Anal/anormalidades , Canal Anal/metabolismo , Craniossinostoses/genética , Nanismo/etiologia , Nanismo/genética , Nanismo/metabolismo , Éxons , Estudos de Associação Genética , Instabilidade Genômica , Comunicação Interatrial/etiologia , Comunicação Interatrial/genética , Comunicação Interatrial/metabolismo , Humanos , Deformidades Congênitas dos Membros/etiologia , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/metabolismo , Patela/anormalidades , Patela/metabolismo , Rádio (Anatomia)/anormalidades , Rádio (Anatomia)/metabolismo , RecQ Helicases/metabolismo , Síndrome de Rothmund-Thomson/etiologia , Síndrome de Rothmund-Thomson/genética , Síndrome de Rothmund-Thomson/metabolismoRESUMO
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.
Assuntos
Síndrome de Cockayne/etiologia , Dano ao DNA , Raios Ultravioleta/efeitos adversos , Ataxia Telangiectasia/etiologia , Síndrome de Bloom/etiologia , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Reparo do DNA , Anemia de Fanconi/etiologia , Feminino , Humanos , Masculino , Modelos Biológicos , Estresse Oxidativo/efeitos da radiação , Progéria/etiologia , Síndrome de Rothmund-Thomson/etiologia , Síndromes de Tricotiodistrofia/etiologia , Síndrome de Werner/etiologia , Xeroderma Pigmentoso/etiologiaRESUMO
The molecular mechanisms leading to human senescence are still not known mostly because of the complexity of the process. Different research approaches are used to study ageing including studies of monogenic segmental progeroid syndromes. None of the known progerias represents true precocious ageing. Some of them, including Werner (WS), Bloom (BS), and Rothmund-Thomson syndromes (RTS) as well as combined xeroderma pigmentosa-Cockayne syndrome (XP-CS) are characterised by features resembling precocious ageing and the increased risk of malignant disease. Such phenotypes result from the mutations of the genes encoding proteins involved in the maintenance of genomic integrity, in most cases DNA helicases. Defective functioning of these proteins affects DNA repair, recombination, replication and transcription. Other segmental progeroid syndromes, such as Hutchinson-Gilford progeria (HGPS) and Cockayne syndrome are not associated with an increased risk of cancer. In this paper we present the clinical and molecular features of selected progeroid syndromes and describe the potential implications of these data for studies of ageing and cancer development.
Assuntos
Senilidade Prematura/genética , Envelhecimento/genética , Síndrome de Bloom/etiologia , Síndrome de Bloom/genética , Síndrome de Cockayne/etiologia , Síndrome de Cockayne/genética , Humanos , Progéria/etiologia , Progéria/genética , Síndrome de Rothmund-Thomson/etiologia , Síndrome de Rothmund-Thomson/genética , Síndrome de Werner/etiologia , Síndrome de Werner/genéticaRESUMO
Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by skin abnormalities that appear in infancy, skeletal abnormalities, juvenile cataracts and other manifestations of premature aging, and a predisposition to malignancy. The diagnosis is made on clinical grounds as no consistent laboratory test has been identified. Chromosome studies have been reported for only three patients with RTS and in two of these three, trisomy 8 mosaicism was found. We performed a variety of cytogenetic and molecular genetic studies on two siblings with RTS and on their phenotypically normal parents. Two chromosomally abnormal clones involving either trisomy 8 or i(8q) were found in both patients with RTS. These clones were present in vivo, as they were seen in interphase buccal smears and lymphocytes from unstimulated preparations using both conventional cytogenetic studies and fluorescence in situ hybridization (FISH) with a centromere probe for chromosome 8. These results suggest that RTS is associated with in vivo clonal chromosomal rearrangements causing an acquired somatic mosaicism.
Assuntos
Mosaicismo/genética , Síndrome de Rothmund-Thomson/etiologia , Síndrome de Rothmund-Thomson/genética , Adolescente , Adulto , Aberrações Cromossômicas , Feminino , Genes p53 , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Linhagem , Síndrome de Rothmund-Thomson/tratamento farmacológico , Sarcoma/complicações , Sarcoma/tratamento farmacológicoRESUMO
The Rothmund-Thomson syndrome is a rare autosomal recessive condition. It is primarily a clinical diagnosis with manifestations that include poikiloderma, short stature, sparse hair, juvenile cataracts, small hands and feet, bone defects, photosensitivity, hypogonadism, defective dentition, onychodystrophy, and hyperkeratosis. There is only one published case of associated gastrointestinal abnormalities. We report a patient with Rothmund-Thomson syndrome with annular pancreas and duodenal stenosis.
Assuntos
Obstrução Duodenal/etiologia , Pancreatopatias/complicações , Síndrome de Rothmund-Thomson/etiologia , Obstrução Duodenal/diagnóstico , Humanos , Lactente , Masculino , Pancreatopatias/congênito , Pancreatopatias/diagnóstico , Síndrome de Rothmund-Thomson/diagnósticoRESUMO
Two patients with juvenile dermatomyositis, 5 with chronic discoid lupus erythematosus, and one with Rothmund-Thomson's Syndrome were treated for their teleangiectasias of the face with argon laser. The results were highly satisfactory with an almost normal appearance of treated skin in 4 patients. Two patients showed satisfactory results with 60-70% blanching, while 2 patients showed some improvement, but not a completely cosmetically satisfactory result. The most impressive results were in the patients with juvenile dermatomyositis and Rothmund-Thomson's Syndrome. The only side effects observed were a slight scarring and an insignificant pigmentation. No patient displayed any signs of disease activation.