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Am J Hum Genet ; 105(4): 803-812, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564438


Concurrent hearing and genetic screening of newborns is expected to play important roles not only in early detection and diagnosis of congenital deafness, which triggers intervention, but also in predicting late-onset and progressive hearing loss and identifying individuals who are at risk of drug-induced HL. Concurrent hearing and genetic screening in the whole newborn population in Beijing was launched in January 2012. This study included 180,469 infants born in Beijing between April 2013 and March 2014, with last follow-up on February 24, 2018. Hearing screening was performed using transiently evoked otoacoustic emission (TEOAE) and automated auditory brainstem response (AABR). For genetic testing, dried blood spots were collected and nine variants in four genes, GJB2, SLC26A4, mtDNA 12S rRNA, and GJB3, were screened using a DNA microarray platform. Of the 180,469 infants, 1,915 (1.061%) were referred bilaterally or unilaterally for hearing screening; 8,136 (4.508%) were positive for genetic screening (heterozygote, homozygote, or compound heterozygote and mtDNA homoplasmy or heteroplasmy), among whom 7,896 (4.375%) passed hearing screening. Forty (0.022%) infants carried two variants in GJB2 or SLC26A4 (homozygote or compound heterozygote) and 10 of those infants passed newborn hearing screening. In total, 409 (0.227%) infants carried the mtDNA 12S rRNA variant (m.1555A>G or m.1494C>T), and 405 of them passed newborn hearing screening. In this cohort study, 25% of infants with pathogenic combinations of GJB2 or SLC26A4 variants and 99% of infants with an m.1555A>G or m.1494C>T variant passed routine newborn hearing screening, indicating that concurrent screening provides a more comprehensive approach for management of congenital deafness and prevention of ototoxicity.

Proc Natl Acad Sci U S A ; 113(21): 5993-8, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27162350


Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.

Células Ciliadas Auditivas/metabolismo , Perda Auditiva Neurossensorial/metabolismo , Mutação , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Gânglio Espiral da Cóclea/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Linhagem Celular , Células Ciliadas Auditivas/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Humanos , Camundongos , Camundongos Mutantes , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Gânglio Espiral da Cóclea/patologia , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo
Proc Natl Acad Sci U S A ; 108(36): 14902-7, 2011 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-21746931


Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 up-regulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5' of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.

Linfócitos B/metabolismo , Proliferação de Células , Infecções por Vírus Epstein-Barr/metabolismo , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Elementos de Resposta , Transcrição Genética , Proteínas Virais/metabolismo , Linfócitos B/virologia , Linhagem Celular Tumoral , Subunidades alfa de Fatores de Ligação ao Core/genética , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Infecções por Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/genética , Genoma Viral/genética , Herpesvirus Humano 4/genética , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Nucleossomos/genética , Nucleossomos/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Proteínas Virais/genética