RESUMO
The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth condition comprising "coarseness" of facial traits, supernumerary nipples, congenital heart defects, polydactyly and fingernail hypoplasia, and an increased risk of neonatal death and later neoplasia. Psychomotor development is usually normal. The syndrome is caused by mutation/deletion of the X-linked gene GPC3. We describe a new case of SGBS, that led to the discovery of an extended family segregating a GPC3 mutation and, ultimately, of an affected relative forgotten, but not lost, in an anatomical museum, where he was classified as a macrosomic newborn, who was born probably around 1940 and died neonatally of unknown cause. This baby boy becomes the oldest case of SGBS on record.
Assuntos
Glipicanas/genética , Padrões de Herança/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Sequência de Bases , Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Dados de Sequência Molecular , Museus , Linhagem , Análise de Sequência de DNAAssuntos
Acetilcarnitina/uso terapêutico , Carnitina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Células Cultivadas , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Nootrópicos/uso terapêutico , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
Most fragile X syndrome patients have expansion of a (CGG)(n)sequence with >200 repeats (full mutation) in the FMR1 gene responsible for this condition. Hypermethylation of the expanded repeat and of the FMR1 promoter is almost always present and apparently suppresses transcription, resulting in absence of the FMR1 protein. We recently showed that transcriptional reactivation of FMR1 full mutations can be achieved by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC). The level of histone acetylation is another important factor in regulating gene expression; therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation patients with three drugs capable of inducing histone hyperacetylation. We observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR. However, we report that combining these drugs with 5-azadC results in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations.
Assuntos
Metilação de DNA , Síndrome do Cromossomo X Frágil/genética , Histonas/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Acetilação , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Sequência de Bases , Linhagem Celular , Primers do DNA , Decitabina , Inibidores Enzimáticos/farmacologia , Proteína do X Frágil da Deficiência Intelectual , Inibidores de Histona Desacetilases , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVES: The risk of uniparental disomy (UPD) occurrence associated with the prenatal finding of balanced nonhomologous Robertsonian translocations (NHRTs) has been estimated only on limited empirical data. The aim of the study was to verify the estimate of the general risk, to get narrower confidence intervals by cumulating the data and to obtain risk estimates for specific translocation types. METHODS: We tested for UPD 160 prenatal specimens referred to the participant centers after the cytogenetic finding of NHRT. RESULTS: One case of upd(14)mat was found, associated with a 45,XX,der(14;22)mat fetal karyotype. The general empirical risk of UPD occurrence in NHRT carrier fetuses, corrected for the actual number of chromosomes analyzed, was 0.76% (95% CI 0.02-4.25%). Cumulative data with previous studies gives a general risk of UPD associated with NHRT of 0.80% (95% CI 0.17-2.34%). The UPD risk for the specific NHRT der(13;14) did not significantly differ from that of the other NHRTs taken together. CONCLUSION: The present survey confirms the previously estimated risk of occurrence of UPD in offspring of NHRT carriers as a low, but not negligible risk, worth being investigated in prenatal diagnosis.