RESUMO
The chromosomal region 14q32 contains several imprinted genes, which are expressed either from the paternal (DLK1 and RTL1) or the maternal (MEG3, RTL1as and MEG8) allele only. Imprinted expression of these genes is regulated by two differentially methylated regions (DMRs), the germline DLK1/MEG3 intergenic (IG)-DMR (MEG3/DLK1:IG-DMR) and the somatic MEG3-DMR (MEG3:TSS-DMR), which are methylated on the paternal and unmethylated on the maternal allele. Disruption of imprinting in the 14q32 region results in two clinically distinct imprinting disorders, Temple syndrome (TS14) and Kagami-Ogata syndrome (KOS14). Another DMR with a yet unknown function is located in intron 2 of MEG8 (MEG8-DMR, MEG8:Int2-DMR). In contrast to the IG-DMR and the MEG3-DMR, this somatic DMR is methylated on the maternal chromosome and unmethylated on the paternal chromosome. We have performed extensive methylation analyses by deep bisulfite sequencing of the IG-DMR, MEG3-DMR and MEG8-DMR in different prenatal tissues including amniotic fluid cells and chorionic villi. In addition, we have studied the methylation pattern of the MEG8-DMR in different postnatal tissues. We show that the MEG8-DMR is hypermethylated in each of 13 non-deletion TS14 patients (seven newly identified and six previously published patients), irrespective of the underlying molecular cause, and is always hypomethylated in the four patients with KOS14, who have different deletions not encompassing the MEG8-DMR itself. The size and the extent of the deletions and the resulting methylation pattern suggest that transcription starting from the MEG3 promoter may be necessary to establish the methylation imprint at the MEG8-DMR.
Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Metilação de DNA , Impressão Genômica , RNA Nucleolar Pequeno/genética , Adulto , Idoso , Transtornos Cromossômicos/diagnóstico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , RNA Nucleolar Pequeno/metabolismoRESUMO
Maternal uniparental disomy 14 [upd(14)mat] is associated with a recognizable phenotype that includes pre- and postnatal growth retardation, neonatal hypotonia, feeding problems and precocious puberty. Chromosome 14 contains an imprinted gene cluster, which is regulated by a differentially methylated region (IG-DMR) between DLK1 and GTL2. Here we report on four patients with clinical features of upd(14)mat who show a maternal-only methylation pattern, but biparental inheritance for chromosome 14. In three of the patients loss of paternal methylation appears to be a primary epimutation, whereas the other patient has a paternally derived deletion of -1 Mb that includes the imprinted DLK1-GTL2 gene cluster. These findings demonstrate that the upd(14)mat phenotype is caused by altered expression of genes within this cluster.
Assuntos
Cromossomos Humanos Par 14/genética , Epigênese Genética , Mutação , Dissomia Uniparental/genética , Adulto , Proteínas de Ligação ao Cálcio , Criança , Metilação de DNA , Análise Mutacional de DNA , Feminino , Deleção de Genes , Impressão Genômica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Membrana , Mães , Família Multigênica , Proteínas , RNA Longo não Codificante , Dissomia Uniparental/fisiopatologiaAssuntos
Homozigoto , Distrofia Miotônica/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/enzimologia , Miotonina Proteína Quinase , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Premutations in the FMR1 gene may be associated with some cases of parkinsonism. To test this hypothesis, we determined the CGG repeat number in FMR1 in 673 individuals with and without parkinsonism and detected 3 premutation carriers (2 patients, 1 control). Of note, 1 of the affected premutation carriers had a heterozygous Parkin mutation.
