RESUMO
Kinesins are a family of proteins for anterograde transport of the molecules from the neuronal cell body and their impairment has been widely associated with neurodegeneration of the motor neurons. KIF5A gene causes autosomal dominant spastic paraplegia 10, a neurological disorder characterized by spasticity and weakness of the lower limbs (SPG10). We carried out a screening of KIF5A gene in 50 subjects affected by HSP negative to diagnostic test for SPG4, ATL1 and REEP1. We identified a novel variation p.Ile255Met in a 58-year-old man who developed progressive gait disturbance due to spastic paraparesis complicated by axonal neuropathy.
Assuntos
Cinesinas/genética , Mutação , Paraplegia Espástica Hereditária/genética , Feminino , Humanos , Itália , Masculino , LinhagemAssuntos
Saúde da Família , Transtornos Mentais/genética , Oxigenases de Função Mista/genética , Mutação/genética , Paraplegia Espástica Hereditária/genética , Análise Mutacional de DNA , Exoma/genética , Humanos , Estudos Longitudinais , Masculino , Transtornos Mentais/complicações , Pessoa de Meia-Idade , Paraplegia Espástica Hereditária/complicaçõesRESUMO
Hereditary spastic paraplegia (HSP) includes a group of diseases characterized by progressive spastic weakness of the lower limbs (pure forms) with possible additional signs (complicated forms). The SPG10 form is due to alteration in the kinesin1A gene (KIF5A) that encodes the neuronal kinesin heavy chain, a protein required for the anterograde axonal transport. We performed clinical, neurophysiological and molecular studies in two siblings affected by AD-HSP complicated by deafness. The screening of the KIF5A gene revealed the novel mutation p.Leu259Gln in two affected siblings and in their father with a pure form of HSP.
Assuntos
Saúde da Família , Perda Auditiva Neurossensorial/genética , Cinesinas/genética , Mutação/genética , Paraparesia Espástica/genética , Adulto , Análise Mutacional de DNA , Feminino , Perda Auditiva Neurossensorial/complicações , Humanos , Itália , Masculino , Neurofisiologia , Paraparesia Espástica/complicaçõesRESUMO
CADASIL is a cerebrovascular disease caused by mutations in the NOTCH3 gene. Most mutations result in a gain or loss of cysteine residue in one of the 34 epidermal growth factor-like repeats in the extracellular domain of the Notch3 protein, thus sparing the number of cysteine residues. To date, more than 130 different mutations in the NOTCH3 gene have been reported in CADASIL patients, of which 95% are missense point mutations. Many polymorphisms have also been identified in the NOTCH3 coding sequence, some of them leading to amino acid substitutions. The aim of the present study was to analyze the NOTCH3 gene in a large group of patients affected by leukoencephalopathy and to investigate the presence of genetic variants. The molecular analysis revealed several nucleotide alterations. In particular, we identified 20 different mutations, 22 polymorphisms, and 8 genetic variants of unknown pathological significance never reported previously. We hope that this NOTCH3 gene mutational analysis, performed in such a significant number of unrelated and related patients affected by leukoencephalopathy, will help in molecular screening for the NOTCH3 gene, thus contributing to enlargement of the NOTCH3 gene variation database.
Assuntos
CADASIL/genética , Receptores Notch/genética , Análise Mutacional de DNA , Humanos , Mutação , Polimorfismo Genético , Receptor Notch3RESUMO
The distal hereditary motor neuropathy (dHMN) is a rare genetically and clinically heterogeneous disorder characterized by weakness and wasting of distal limb muscles in absence of overt sensory abnormalities. Recently, pyramidal signs have been also described in some patients with dominant or recessive dHMN, and two different loci have been identified in families affected by dHMN complicated with pyramidal dysfunction. We investigated an Italian family affected by an autosomal dominant dHMN complicated by pyramidal signs in order to map a new gene locus. The disease maps to a novel locus in a 26-cM region flanked by D4S1552 and D4S2930 on chromosome 4q34.3-35.2. Three candidate genes (SNX25, CASP3 and TUBB4Q) located in the critical region were screened for the presence of mutations by heteroduplex analysis. No mutations have been detected in the analyzed genes. In conclusion, the new private genetic locus we reported further confirms the wide heterogeneity of dHMN.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 4/genética , Neuropatia Hereditária Motora e Sensorial/genética , Feminino , Heterogeneidade Genética , Ligação Genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Masculino , LinhagemRESUMO
Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.
Assuntos
Esclerose Lateral Amiotrófica/genética , Predisposição Genética para Doença/genética , Neurônios Motores/metabolismo , Mutação/genética , Ribonuclease Pancreático/genética , Adulto , Idoso , Substituição de Aminoácidos/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/fisiopatologia , Mapeamento Cromossômico , Cromossomos Humanos Par 14/genética , Citoproteção/genética , Análise Mutacional de DNA , Feminino , Ligação Genética/genética , Marcadores Genéticos/genética , Testes Genéticos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Neurônios Motores/patologia , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Ribonuclease Pancreático/químicaAssuntos
Encéfalo/patologia , CADASIL/genética , Mutação INDEL/genética , Mutação de Sentido Incorreto/genética , Receptores Notch/genética , Adulto , CADASIL/diagnóstico , CADASIL/fisiopatologia , Feminino , Lobo Frontal/patologia , Humanos , Imageamento por Ressonância Magnética , Linhagem , Fenótipo , Receptor Notch3 , Lobo Temporal/patologiaRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.
Assuntos
CADASIL/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Superfície Celular/genética , Deleção de Sequência , Adulto , Idoso , CADASIL/patologia , Cromatografia Líquida de Alta Pressão , Cisteína/química , Éxons/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Dobramento de Proteína , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/química , Receptor Notch3 , Receptores de Superfície Celular/química , Receptores Notch , Sequências Repetitivas de Aminoácidos , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To investigate the possible occurrence of a conversion event in three patients with adult-onset spinal muscular atrophy (SMA) type IV, which represents the mildest form within the spectrum of the SMA phenotype. MATERIAL AND METHODS: We observed three patients with adult onset SMA and apparent isolated deletion of telomeric survival motor neuron (SMN1) exon 7. To distinguish between a deletion and a sequence conversion event of exon 7, these patients were analyzed in greater detail by a simple PCR-based assay. RESULTS: Analysis by DdeI digestion showed products for both telomeric and centromeric copies of exon 8. These findings indicated a gene conversion event as the site for primer R111 was retained at least in one of two alleles. CONCLUSIONS: These results provide first evidence that a conversion event may be also associated with adult-onset SMA, and further support the notion that a gene conversion event is usually associated with a milder SMA phenotype and a later onset of disease.
Assuntos
Deleção de Genes , Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idade de Início , Idoso , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Éxons , Humanos , Masculino , Atrofia Muscular Espinal/patologia , Fenótipo , Reação em Cadeia da Polimerase , Proteínas de Ligação a RNA , Proteínas do Complexo SMN , Índice de Gravidade de Doença , Proteína 1 de Sobrevivência do Neurônio Motor , Telômero/genéticaRESUMO
Hereditary spastic paraplegias are neurodegenerative disorders characterized clinically by progressive spasticity of the lower limbs. They are inherited as autosomal dominant, autosomal recessive, and X-linked traits. Four Italian families with autosomal recessive pure spastic paraplegia are reported. We show evidence of linkage to the SPG5 locus on chromosome 8p and our data reduce the candidate interval for SPG5 to the11-cM interval spanned by D8S285 and D8S544. We also report the search for mutations in five genes located in the region and their exclusion as candidates for SPG5.
Assuntos
Cromossomos Humanos Par 8 , Escore Lod , Paraplegia/genética , Adulto , Saúde da Família , Feminino , Genes Recessivos , Marcadores Genéticos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4. OBJECTIVES: To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADASIL, and to report the results of magnetic resonance spectroscopy in CADASIL. METHODS: Mutation analysis of the Notch3 gene was performed in 2 patients belonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes. Proton magnetic resonance spectroscopy was used to estimate metabolite resonance intensities in the 2 affected subjects. RESULTS: Sequence analysis of the Notch3 gene showed a new missense mutation CGC-->TGC in codon 332 of exon 6, resulting in the replacement of an arginine residue with a cysteine. This mutation was never observed in the 7 unaffected members of the family and the 200 control chromosomes examined. Proton magnetic resonance spectroscopy showed a diffuse decrease in cerebral N-acetylaspartate, indicating the presence of widespread axonal damage. CONCLUSIONS: Our findings emphasize the role of direct DNA sequence analysis for the diagnosis of CADASIL. Moreover, the results of proton magnetic resonance spectroscopy suggest that widespread axonal damage may be an early finding of the disease.
