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1.
Hum Mutat ; 35(1): 58-62, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24130152

RESUMO

A 0.8 kb intronic duplication in MAGT1 and a single base pair deletion in the last exon of ATRX were identified using a chromosome X-specific microarray and exome sequencing in a family with five males demonstrating intellectual disability (ID) and unusual skin findings (e.g., generalized pruritus). MAGT1 is an Mg²âº transporter previously associated with primary immunodeficiency and ID, whereas mutations in ATRX cause ATRX-ID syndrome. In patient cells, the function of ATRX was demonstrated to be abnormal based on altered RNA/protein expression, hypomethylation of rDNA, and abnormal cytokinesis. Dysfunction of MAGT1 was reflected in reduced RNA/protein expression and Mg²âº influx. The mutation in ATRX most likely explains the ID, whereas MAGT1 disruption could be linked to abnormal skin findings, as normal magnesium homeostasis is necessary for skin health. This work supports observations that multiple mutations collectively contribute to the phenotypic variability of syndromic ID, and emphasizes the importance of correlating clinical phenotype with genomic and cell function analyses.


Assuntos
Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prurido/genética , Cromossomos Humanos X , Citocinese , Metilação de DNA , DNA Ribossômico/metabolismo , Exoma , Feminino , Genes Duplicados , Humanos , Íntrons , Magnésio/metabolismo , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Mutação Puntual , Prurido/patologia , Análise de Sequência de DNA , Síndrome , Proteína Nuclear Ligada ao X
2.
Epigenetics Chromatin ; 4(1): 10, 2011 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-21749726

RESUMO

BACKGROUND: Genomic imprinting is an important epigenetic process involved in regulating placental and foetal growth. Imprinted genes are typically associated with differentially methylated regions (DMRs) whereby one of the two alleles is DNA methylated depending on the parent of origin. Identifying imprinted DMRs in humans is complicated by species- and tissue-specific differences in imprinting status and the presence of multiple regulatory regions associated with a particular gene, only some of which may be imprinted. In this study, we have taken advantage of the unbalanced parental genomic constitutions in triploidies to further characterize human DMRs associated with known imprinted genes and identify novel imprinted DMRs. RESULTS: By comparing the promoter methylation status of over 14,000 genes in human placentas from ten diandries (extra paternal haploid set) and ten digynies (extra maternal haploid set) and using 6 complete hydatidiform moles (paternal origin) and ten chromosomally normal placentas for comparison, we identified 62 genes with apparently imprinted DMRs (false discovery rate <0.1%). Of these 62 genes, 11 have been reported previously as DMRs that act as imprinting control regions, and the observed parental methylation patterns were concordant with those previously reported. We demonstrated that novel imprinted genes, such as FAM50B, as well as novel imprinted DMRs associated with known imprinted genes (for example, CDKN1C and RASGRF1) can be identified by using this approach. Furthermore, we have demonstrated how comparison of DNA methylation for known imprinted genes (for example, GNAS and CDKN1C) between placentas of different gestations and other somatic tissues (brain, kidney, muscle and blood) provides a detailed analysis of specific CpG sites associated with tissue-specific imprinting and gestational age-specific methylation. CONCLUSIONS: DNA methylation profiling of triploidies in different tissues and developmental ages can be a powerful and effective way to map and characterize imprinted regions in the genome.

3.
Prenat Diagn ; 30(1): 1-8, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19918961

RESUMO

OBJECTIVE: Prenatally diagnosed confined placental trisomy is associated with increased risk for intrauterine growth restriction (IUGR) and preeclampsia. However, it is unclear how often this might underlie pregnancy complications. Our objective was to evaluate the frequency and distribution of trisomic cells in placentae ascertained for IUGR and/or preeclampsia. METHOD: Comparative genomic hybridization was applied to two uncultured biopsies from each of 61 placentae referred with maternal preeclampsia and/or IUGR, 11 cases with elevated maternal serum hCG and/or AFP but no IUGR or preeclampsia, and 85 control placentae. RESULTS: Trisomy was observed in four placentae among the IUGR group (N = 43) but in no case of preeclampsia in the absence of IUGR (N = 18). Trisomy was observed in 1 of the 11 cases ascertained for abnormal maternal serum screen. Each of these five cases was mosaic and not all sampled sites showed the presence of trisomy. None of the 84 control placentas showed mosaic trisomy, although 1 case of nonmosaic 47,XXX was identified in this group. CONCLUSION: In cases in which diagnosis of the cause of IUGR may provide some benefit, testing should be performed using uncultured cells from multiple placental biopsies for the accurate diagnosis of trisomy mosaicism.


Assuntos
Retardo do Crescimento Fetal/genética , Predisposição Genética para Doença , Placenta/patologia , Pré-Eclâmpsia/genética , Trissomia/genética , Adulto , Biópsia , Gonadotropina Coriônica/sangue , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 7 , Hibridização Genômica Comparativa/métodos , Feminino , Retardo do Crescimento Fetal/sangue , Idade Gestacional , Humanos , Mosaicismo , Pré-Eclâmpsia/sangue , Gravidez , Resultado da Gravidez , Diagnóstico Pré-Natal , Trissomia/patologia
4.
Autism Res ; 1(3): 169-78, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19132145

RESUMO

Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were peformed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCTC-binding factor (CTCF) bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/patologia , Encéfalo/patologia , Cromossomos Humanos X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Metilação , Inativação do Cromossomo X/genética , Pré-Escolar , Primers do DNA/genética , Humanos , Polimorfismo Genético/genética
6.
Hum Reprod ; 17(12): 3037-8, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12456599

RESUMO

Triploidy may arise from either digynic or diandric fertilizations. Errors in the second meiotic division account for most digynic triploidy while most studies have found that approximately 2/3 of diandric triploids arise as the result of dispermy and 1/3 as the result of meiotic errors giving rise to diploid sperm. Using molecular markers very close to the centromere, all 14 cases of diandric triploidy were shown to be the result of dispermy with no evidence to support a meiotic error as the origin of diandric triploids.


Assuntos
Fertilização , Poliploidia , Espermatozoides , Centrômero , Diploide , Feminino , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Masculino , Meiose
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