RESUMO
We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.
Assuntos
Éxons/genética , Demência Frontotemporal/genética , Estudos de Associação Genética/métodos , Heterozigoto , Íntrons/genética , Transtornos Parkinsonianos/genética , Mutação Puntual/genética , Proteínas tau/genética , Idoso , Encéfalo/diagnóstico por imagem , Cromossomos Humanos Par 17/genética , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/genética , Neuroimagem , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Tauopatias/genéticaRESUMO
We report a case of a female child who has classical Freeman-Sheldon syndrome (FSS) associated with a previously reported recurrent pathogenic heterozygous missense mutation, c.2015G > A, p. (Arg672His), in MYH3 where the phenotypically normal mother is a molecularly confirmed mosaic. To the best of our knowledge, this is the first report in the medical literature of molecularly confirmed parental mosaicism for a MYH3 mutation causing FSS. Since proven somatic mosaicism after having an affected child is consistent with gonadal mosaicism, a significantly increased recurrence risk is advised. Parental testing is thus essential for accurate risk assessment for future pregnancies and the use of new technologies with next generation sequencing (NGS) may improve the detection rate of mosaicism. © 2016 Wiley Periodicals, Inc.
Assuntos
Disostose Craniofacial/diagnóstico , Disostose Craniofacial/genética , Proteínas do Citoesqueleto/genética , Estudos de Associação Genética , Mosaicismo , Mutação , Fenótipo , Alelos , Substituição de Aminoácidos , Audiometria , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Ecocardiografia , Feminino , Genótipo , Humanos , Recém-Nascido , Exame FísicoRESUMO
Malignant peripheral nerve sheath tumor is a rare malignancy, accounting for 3% to 10% of all soft-tissue sarcomas. We describe a previously healthy 48-year-old man who was diagnosed as having a high-grade malignant neoplasm involving the facial nerve in the right petrous canal after a 4-year history of deafness. The tumor was resected; histologic appearance and immunophenotype, including patchy but strong positivity for S100 protein, indicated a diagnosis of malignant peripheral nerve sheath tumor. A PTEN mutation, c.1003C>T p.(Arg335Ter), was subsequently identified as the cause of Cowden syndrome in another family member (a nephew) with dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease), and genetic testing in the proband's daughter indicated that he was an obligate carrier of the mutation. Sequencing of the tumor showed homozygosity for c.1003C>T, confirming the presence of a germline mutation and implying loss of the second allele. With the exception of Lhermitte-Duclos disease, tumors of the nervous system are not a prominent feature of Cowden syndrome, and this is the first report of malignant peripheral nerve sheath tumor in Cowden syndrome. Sequencing results in the tumor lend evidence to PTEN gene inactivation being implicated in tumorigenesis in this case, suggesting causality rather than chance association.
Assuntos
Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/diagnóstico , Neoplasias de Bainha Neural/complicações , Neoplasias de Bainha Neural/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Bainha Neural/genética , LinhagemRESUMO
In all metazoan organisms, the diversification of cell types involves determination of cell fates and subsequent execution of specific differentiation programs. During Drosophila myogenesis, identity genes specify the fates of founder myoblasts, from which derive all individual larval muscles. Here, to understand how cell fate information residing within founders is translated during differentiation, we focus on three identity genes, eve, lb, and slou, and how they control the size of individual muscles by regulating the number of fusion events. They achieve this by setting expression levels of Mp20, Pax, and mspo, three genes that regulate actin dynamics and cell adhesion and, as we show here, modulate the fusion process in a muscle-specific manner. Thus, these data show how the identity information implemented by transcription factors is translated via target genes into cell-type-specific programs of differentiation.