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1.
BMC Med Genet ; 17(1): 66, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27634379

RESUMO

BACKGROUND: The main form of Facio-Scapulo-Humeral muscular Dystrophy is linked to copy number reduction of the 4q D4Z4 macrosatellite (FSHD1). In 5 % of cases, FSHD phenotype appears in the absence of D4Z4 reduction (FSHD2). In 70-80 % of these patients, variants of the SMCHD1 gene segregate with 4qA haplotypes and D4Z4 hypomethylation. CASE PRESENTATION: We report a family presenting with neuromuscular symptoms reminiscent of FSHD but without D4Z4 copy reduction. We characterized the 4q35 region using molecular combing, searched for mutation in the SMCHD1 gene and determined D4Z4 methylation level by sodium bisulfite sequencing. We further investigated the impact of the SMCHD1 mutation at the protein level and on the NMD-dependent degradation of transcript. In muscle, we observe moderate but significant reduction in D4Z4 methylation, not correlated with DUX4-fl expression. Exome sequencing revealed a heterozygous insertion of 7 bp in exon 37 of the SMCHD1 gene producing a loss of frame with premature stop codon 4 amino acids after the insertion (c.4614-4615insTATAATA). Both wild-type and mutated transcripts are detected. CONCLUSION: The truncated protein is absent and the full-length protein level is similar in patients and controls indicating that in this family, FSHD is not associated with SMCHD1 haploinsufficiency.


Assuntos
Proteínas Cromossômicas não Histona/genética , Metilação de DNA , Repetições de Microssatélites , Distrofia Muscular Facioescapuloumeral/genética , Mutação , Segregação de Cromossomos , Cromossomos Humanos Par 4/genética , Humanos , Linhagem
2.
Neurology ; 83(8): 733-42, 2014 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-25031281

RESUMO

OBJECTIVE: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and could not thus far be correlated with disease presence or severity. METHODS: To investigate the link between clinical signs of FSHD and DNA methylation, we explored 95 cases (37 FSHD1, 29 asymptomatic individuals carrying a shortened D4Z4 array, 9 patients with FSHD2, and 20 controls) by implementing 2 approaches: methylated DNA immunoprecipitation and sodium bisulfite sequencing. RESULTS: Both methods revealed statistically significant differences between asymptomatic carriers or controls and individuals with clinical FSHD, especially in the proximal region of the repeat. Absence of clinical expression in asymptomatic carriers is associated with a level of methylation similar to controls. CONCLUSIONS: We provide a proof of concept that the targeted approaches that we describe could be applied systematically to patient samples in routine diagnosis and suggest that local hypomethylation within D4Z4 might serve as a modifier for clinical expression of FSHD phenotype. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that assays for hypomethylation within the D4Z4 region accurately distinguish patients with FSHD from individuals with D4Z4 contraction without FSHD.


Assuntos
Cromossomos Humanos Par 4 , Metilação de DNA/genética , Predisposição Genética para Doença , Distrofia Muscular Facioescapuloumeral/genética , Adulto , Epigênese Genética/genética , Feminino , Testes Genéticos , Heterozigoto , Humanos , Masculino , Distrofia Muscular Facioescapuloumeral/diagnóstico , Linhagem , Penetrância , Fenótipo , Adulto Jovem
3.
J Neurochem ; 106(2): 969-77, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18466332

RESUMO

Members of the striatin family are scaffolding proteins involved in numerous signaling pathways principally in neurons. Zinedin is the only member of this protein family for which the brain distribution has not been determined so far. Here, we have validated a specific antibody against zinedin and used this tool to study the localization of zinedin at cellular and sub-cellular levels in the rat brain. Zinedin is primarily expressed in neurons of the hippocampus, cerebral cortex, olfactory bulb and caudate putamen nucleus. Like other members of the striatin family, zinedin displays a polarized distribution in the somato-dendritic compartment of neurons and is enriched in dendritic spines. The rostral expression of zinedin as well as its compartmented distribution in dendritic spines may have important implications not only for zinedin function but also in the physiology of dendritic spines of a particular subset of neurons.


Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Animais , Autoantígenos/metabolismo , Encéfalo/citologia , Proteínas de Ligação a Calmodulina/genética , Linhagem Celular Transformada , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Microscopia Imunoeletrônica/métodos , Proteínas do Tecido Nervoso/genética , Neurônios/ultraestrutura , Ratos , Transfecção/métodos
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