RESUMO
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.
Assuntos
Lamina Tipo A/metabolismo , Progéria/patologia , Prenilação de Proteína/efeitos dos fármacos , Pirimidinas/farmacologia , Sítios de Ligação , Diferenciação Celular/efeitos dos fármacos , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/metabolismo , Geraniltranstransferase/antagonistas & inibidores , Geraniltranstransferase/metabolismo , Humanos , Lamina Tipo A/antagonistas & inibidores , Lamina Tipo A/genética , Simulação de Acoplamento Molecular , Osteogênese/efeitos dos fármacos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Progéria/metabolismo , Estrutura Terciária de Proteína , Pirimidinas/química , Pirimidinas/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2-q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. Our results indicate that the affected individuals share a common ancestral haplotype in a region of about 1.0 Mb (1 cM) and that the most recent common ancestor would have lived about 800-900 years ago (95% confidence interval: 550 to 1300 years).
Assuntos
Doença de Charcot-Marie-Tooth/genética , Efeito Fundador , Lamina Tipo A/genética , Mutação de Sentido Incorreto , Argélia , Substituição de Aminoácidos , Feminino , Homozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Sequências de Repetição em Tandem , Fatores de TempoRESUMO
BACKGROUND: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. METHODS: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. RESULTS: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. CONCLUSIONS: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.
Assuntos
Anormalidades Múltiplas/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/genética , Proto-Oncogene Mas , SíndromeAssuntos
Blefaroptose/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 2/genética , Predisposição Genética para Doença , Oftalmoplegia/genética , Translocação Genética , Criança , Mapeamento Cromossômico , Segregação de Cromossomos , Feminino , Fibrose , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Músculos Oculomotores/patologia , Oftalmoplegia/congênito , Oftalmoplegia/patologia , LinhagemAssuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Doenças Desmielinizantes/genética , Homozigoto , Adulto , Argélia/etnologia , Doença de Charcot-Marie-Tooth/etnologia , Doença de Charcot-Marie-Tooth/patologia , Mapeamento Cromossômico , Doenças Desmielinizantes/etnologia , Doenças Desmielinizantes/patologia , Feminino , Genes Recessivos , Testes Genéticos , Humanos , Líbano/etnologia , Masculino , Linhagem , Nervo Sural/patologiaAssuntos
Doenças Desmielinizantes/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso Periférico/genética , Processamento Alternativo/genética , Axônios/fisiologia , Sequência de Bases , Criança , Códon sem Sentido , Consanguinidade , DNA/química , DNA/genética , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Eletrofisiologia , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Microscopia Eletrônica , Linhagem , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Nervo Fibular/patologia , Nervo Fibular/ultraestrutura , FenótipoRESUMO
Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot-Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot-Marie-Tooth type 2 carrying a mutation in LMNA.
