RESUMO
Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/ß-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re-polymerization. Morpholino-mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone-associated tubulinopathy, and provide insights into the phenotype of this disorder.
Assuntos
Deficiências do Desenvolvimento/genética , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Convulsões/genética , Animais , Pré-Escolar , Embrião não Mamífero , Epilepsia/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/genética , Microtúbulos/patologia , Convulsões/diagnóstico por imagem , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Partial epilepsy with auditory features occasionally segregates in families as an autosomal dominant trait. In some families mutations in the leucine-rich glioma inactivated (LGI1) gene have been identified. Sporadic cases might harbour either denovo or low-penetrant LGI1 mutations, which will substantially alter the family risk for epilepsy. We selected sixteen sporadic patients with cryptogenic temporal lobe epilepsy and partial seizures with auditory features. We compared clinical features of these patients with those of published autosomal dominant family cases. We screened these patients for LGI1 mutations. Comparing the sporadic patients with the published familial cases no difference in either the primary auditory features or in the other associated epileptic manifestations was identified. Sequence analysis of the whole LGI1 gene coding regions in sporadic patients did not reveal changes in the LGI1 gene. The genetic analysis demonstrates that LGI1 is not a major gene for sporadic cases of partial epilepsy with auditory features at least in the Italian population. Screening of sporadic patients for LGI1 mutations appears not useful in genetic counselling of these patients.
Assuntos
Epilepsia Parcial Sensorial/genética , Epilepsia do Lobo Temporal/genética , Predisposição Genética para Doença/genética , Mutação/genética , Proteínas/genética , Adulto , Análise Mutacional de DNA , Epilepsia Parcial Sensorial/diagnóstico , Epilepsia Parcial Sensorial/fisiopatologia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Itália , Masculino , Pessoa de Meia-IdadeAssuntos
Síndrome Brânquio-Otorrenal/genética , Análise Mutacional de DNA/métodos , Mutação/genética , Transativadores/genética , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas Nucleares , Desnaturação de Ácido Nucleico , Proteínas Tirosina FosfatasesRESUMO
Hearing impairment (HI) is the most frequent sensory defect with wide genetic heterogeneity. Approximately 80% of genetic hearing loss is non-syndromic and 15-25% of exhibit autosomal dominant inheritance. We analysed an Italian three generation family in which non-syndromic hearing impairment is transmitted as an autosomal dominant trait. Onset of HI in all affected subjects occurred in the second decade of life, with subsequent gradual progression from moderate to profound loss. HI was bilateral and symmetrical, involving all frequencies. After exclusion of the known DFNA loci with markers from the Hereditary Hearing Loss Homepage (URL: http://dnalab-www.uia.ac.be/dnalab/hhh), a genome wide scan was carried out using 358 highly informative microsatellite markers. Significant linkage (Zmax=4.21, theta=0) was obtained with chromosome 2p12 markers. The results were confirmed by multipoint analysis (Zmax=4.51), using the location score method. Haplotype analysis defined a 9.6 cM disease gene interval on chromosome 2 without overlap with the other identified loci. Fine mapping and identification of candidate genes are in progress.
Assuntos
Cromossomos Humanos Par 2/genética , Genes Dominantes/genética , Perda Auditiva Neurossensorial/genética , Mapeamento Cromossômico , Proteínas do Citoesqueleto/genética , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Ligação Genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Perda Auditiva Neurossensorial/patologia , Humanos , Itália , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , alfa CateninaAssuntos
Cromatografia Líquida de Alta Pressão/métodos , Clonagem Molecular/métodos , Análise Mutacional de DNA/métodos , DNA Bacteriano/química , DNA Bacteriano/genética , Perfilação da Expressão Gênica/métodos , Mutagênese Sítio-Dirigida , DNA Bacteriano/análise , Desnaturação de Ácido Nucleico , Recombinação GenéticaRESUMO
Symphalangism (SYM or SYM1) is an autosomal dominant disorder characterized by multiple joint fusions. The disease is caused by mutations of the NOG gene, that maps to chromosome 17q22. So far, only six independent NOG mutations have been identified. We have analysed an Italian family in which father and son had bilateral symphalangism and detected a novel NOG mutation (P35S), originated in the father from a c.914C>T transition. A different mutation in the same codon (P35R) has been previously described. Comparison between different noggin gene hortologs shows that codon 35 is conserved. Therefore, this codon should play an important role in NOG gene function. This is the first mutation described for NOG after the initial report of NOG mutations being causative of SYM.
Assuntos
Articulações dos Dedos/anormalidades , Mutação/genética , Prolina/genética , Proteínas/genética , Serina/genética , Articulação do Dedo do Pé/anormalidades , Sequência de Aminoácidos/genética , Substituição de Aminoácidos/genética , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/genética , Proteínas de Transporte , Cromossomos Humanos Par 17/genética , Feminino , Haplótipos/genética , Humanos , Itália , Masculino , Dados de Sequência Molecular , Estrutura Secundária de ProteínaRESUMO
Hearing impairment is the most common inherited human sensory defect. Nonsyndromic Hearing Impairment (NSHI) is the most genetically heterogeneous trait known. Over 70 loci have been mapped and a total of 19 genes have been identified. We report here a novel locus (DFNA 30) for autosomal dominant NSHI that we mapped to chromosome 15q25-26 in an Italian four-generation family. The haplotype analysis has identified a critical interval of 18 cM between markers D15S151 and D15S130. This region does not overlap with DFNB16 locus but partially coincides with the otosclerosis (OTS) locus. Localisation of the locus DFNA30 is a first step towards the identification of the gene.