RESUMO
BACKGROUND: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. METHODS: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. RESULTS: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). CONCLUSIONS: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.
Assuntos
Axônios/patologia , Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes/genética , Genes Recessivos/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Idade de Início , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Cromossomos Humanos Par 8/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Eletrofisiologia , Família , Feminino , Ligação Genética/genética , Testes Genéticos , Humanos , Lactente , Masculino , Condução Nervosa/fisiologia , Linhagem , Nervo Sural/patologia , TurquiaAssuntos
Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Genes Dominantes/genética , Adolescente , Adulto , Idade de Início , Idoso , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Feminino , Haplótipos/genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , EspanhaRESUMO
Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.
Assuntos
Aciltransferases/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Esfingosina/análogos & derivados , Acil Coenzima A/metabolismo , Bélgica , Mapeamento Cromossômico , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , Progressão da Doença , Éxons/genética , Feminino , Genes Dominantes , Humanos , Pessoa de Meia-Idade , Mutação , Linhagem , Subunidades Proteicas/genética , Serina/metabolismo , Serina C-Palmitoiltransferase , Esfingosina/biossínteseRESUMO
Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.
Assuntos
Esclerose Lateral Amiotrófica/genética , Neuropatia Hereditária Motora e Sensorial/genética , Tratos Piramidais/fisiopatologia , Adolescente , Adulto , Idoso , Esclerose Lateral Amiotrófica/fisiopatologia , Criança , Cromossomos Humanos Par 9/genética , Feminino , Frequência do Gene/genética , Ligação Genética/genética , Haplótipos/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Charcot-Marie-Tooth disease type 2A (CMT2A) was assigned to a 19.3-cM region on chromosome 1p35-36. A missense mutation in the kinesin family member 1B gene (KIF1B) was reported in a single CMT2A family. OBJECTIVE: To report the clinical and genetic data of a Turkish family with CMT2A. METHODS: Linkage to CMT2 loci was investigated in the family. Haplotype analysis of the CMT2A region was completed using additional single-nucleotide polymorphism and short tandem repeat markers. The KIF1B gene was sequenced on genomic DNA and cDNA in two patients. RESULTS: A recombination event narrowed the CMT2A locus to a 9.3-cM region flanked by D1S160 and D1S434. No mutation in KIF1B was found. CONCLUSION: The exclusion of KIF1B gene mutations in this family suggests the involvement of another CMT2A gene in the linked region.
Assuntos
Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Doença de Charcot-Marie-Tooth/genética , Etnicidade/genética , Cinesinas/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/etnologia , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Família/etnologia , Feminino , Ligação Genética/genética , Marcadores Genéticos/genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Condução Nervosa/fisiologia , Proteínas Nucleares , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sequências de Repetição em Tandem/genética , Turquia/etnologiaRESUMO
Combination therapy with protease (PR) and reverse transcriptase (RT) inhibitors can efficiently suppress human immunodeficiency virus (HIV) replication, but the emergence of drug-resistant variants correlates strongly with therapeutic failure. Here we describe a new method for high-throughput analysis of clinical samples that permits the simultaneous detection of HIV type 1 (HIV-1) phenotypic resistance to both RT and PR inhibitors by means of recombinant virus assay technology. HIV-1 RNA is extracted from plasma samples, and a 2.2-kb fragment containing the entire HIV-1 PR- and RT-coding sequence is amplified by nested reverse transcription-PCR. The pool of PR-RT-coding sequences is then cotransfected into CD4+ T lymphocytes (MT4) with the pGEMT3deltaPRT plasmid from which most of the PR (codons 10 to 99) and RT (codons 1 to 482) sequences are deleted. Homologous recombination leads to the generation of chimeric viruses containing PR- and RT-coding sequences derived from HIV-1 RNA in plasma. The susceptibilities of the chimeric viruses to all currently available RT and/or PR inhibitors is determined by an MT4 cell-3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based cell viability assay in an automated system that allows high sample throughput. The profile of resistance to all RT and PR inhibitors is displayed graphically in a single PR-RT-Antivirogram. This assay system facilitates the rapid large-scale phenotypic resistance determinations for all RT and PR inhibitors in one standardized assay.