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1.
Nat Commun ; 12(1): 1022, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589584

RESUMO

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Mieloma Múltiplo/tratamento farmacológico , Coativador 3 de Receptor Nuclear/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 4 , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Coativador 3 de Receptor Nuclear/antagonistas & inibidores , Coativador 3 de Receptor Nuclear/metabolismo , Inibidores de Proteassoma/farmacologia , Recidiva , Proteínas Repressoras/metabolismo , Transdução de Sinais , Análise de Sobrevida , Translocação Genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Yonsei Med J ; 62(1): 95-98, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33381940

RESUMO

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder characterized by weakness of facial, shoulder, abdominal, hip girdle, humeral, and anterior distal leg muscles, with descending progression from the face to the legs in an asymmetric pattern. In about 5% of patients with FSHD, no D4Z4 repeat contraction on chromosome 4q35 is observed; this disease entity is called FSHD2. FSHD2 is characterized by DNA hypomethylation on the 4q-subtelomeric macrosatellite repeat array D4Z4. In Korea, there have been no previous reports of FSHD2. We report the first two cases of FSHD2 in Korea, carrying c.3801delG and c.1580C>T mutations in the SMCHD1 gene, respectively. For rapid and accurate diagnosis of FSHD2, genetic analysis of the D4Z4 haplotype and methylation with next-generation sequencing are required.


Assuntos
Distrofia Muscular Facioescapuloumeral/genética , Adulto , Cromossomos Humanos Par 4/genética , Metilação de DNA , Feminino , Haplótipos , Humanos , Masculino , Repetições de Microssatélites/genética , Mutação , República da Coreia
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 843-846, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761591

RESUMO

OBJECTIVE: To explore the genetic basis for a child featuring short stature. METHODS: G-banded karyotyping, chromosomal microarray analysis (CMA) and high-throughput sequencing were carried out on peripheral blood sample from the child. RESULTS: The karyotype of the child was ascertained as 45,XY,-4[3]/46,XY,r(4)(p16q35)[84]/47,XY,-4,r(4)(p16q25)*2[7]/48,XY,-4,r(4)(p16q35)*3[1]/46,XY,dic r(4;4)(p16q35;p16q35)[2]/46,XY,add(4)(p16)[3]. A 647 kb deletion at 4p16.3 was identified by CMA, which encompassed 6 OMIM genes including ZNF141, PIGG, PDE6B, ATP5I, PCGF3 and MYL5. High-throughput sequencing has identified no pathogenic/likely pathogenic variants consistent with the clinical symptoms. CONCLUSION: A rare ring chromosome 4 syndrome was identified by combined chromosomal karyotyping, CMA and high-throughput sequencing. Conventional cytogenetic analysis and genetic testing in combine have enabled the diagnosis in this case.


Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cariotipagem , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 4/genética , Humanos , Cromossomos em Anel
5.
DNA Cell Biol ; 39(9): 1583-1594, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32635759

RESUMO

MicroRNAs (miRNAs)-related single-nucleotide polymorphisms (SNPs) have been shown to be implicated in the susceptibility to different types of cancer, including esophageal squamous cell carcinoma (ESCC). Identification of miRNA-related SNPs may provide candidate biomarkers for early diagnosis of ESCC. We performed a genome-wide microarray assay to identify differentially expressed miRNAs, which indicated that the miR-15 family may play an important role in ESCC biology. We then investigated the association of miR-15 family-related SNPs with ESCC. Five miR-15 family-related SNPs were genotyped in 300 patients and 418 controls. Unconditional logistic regression was used to evaluate the relationships of these SNPs with ESCC. Generalized multifactor dimensionality reduction was employed to analyze the SNP-SNP and SNP-smoking interactions. The expression quantitative trait loci (eQTL) databases were queried for in silico functional validation. We found that miR-15b SNP rs1451761T>G was associated with a significantly decreased risk of ESCC and there was a significant SNP-SNP interaction between rs1451761 and rs2740545. SNP-smoking interaction analysis also indicated that the association between rs1451761 and ESCC risk could be changed by smoking status. Additionally, the eQTL analysis revealed that rs1451761 was significantly correlated with structural maintenance of chromosomes 4 and karyopherin subunit alpha 4 mRNA expression. Our results suggest that miR-15b SNP rs1451761 may affect an individual's susceptibility to ESCC, alone and in SNP-SNP and SNP-smoking interaction manners.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Carcinoma de Células Escamosas/epidemiologia , Cromossomos Humanos Par 4/genética , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Locos de Características Quantitativas , Fumar/epidemiologia , alfa Carioferinas/genética , alfa Carioferinas/metabolismo
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(7): 731-735, 2020 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-32619252

RESUMO

OBJECTIVE: To analyze ultrasonographic finding in fetuses with Wolf-Hirschhorn syndrome (WHS) and refine the critical region on chromosome 4p16.3 for WHS-associated fetal growth retardation (FGR). METHODS: In total 2262 fetuses with abnormal ultrasonographic findings who underwent prenatal karyotyping and chromosomal microarray analysis were reviewed. WHS-associated 4p deletions detected in these fetuses were compared, and prenatal ultrasound findings in such fetuses were summarized. Meanwhile, WHS cases with prenatal ultrasound findings and isolated 4p deletions in previous studies were included for further analysis. An analysis of smallest region of overlap (SRO) among discrepant 4p deletions in these cases above was performed to define a critical region for FGR. RESULTS: 4p deletions were detected in 10 of the 2262 fetuses and 5.0% of the 202 fetuses with FGR. Combined with 80 WHS cases from previous studies, the most common prenatal ultrasound finding was FGR, which yielded a frequency of 76.7%. In addition, a SRO spanning approximately 419 kb (genomic position: 1.32-1.74 Mb) on chromosome 4p16.3 was discovered by comparing the unusual 4p deletions among the 10 fetuses. The region contained seven protein-coding genes, including TACC3, SLBP, TMEM129, FAM53A, MAEA, UVSSA and CRIPAK. CONCLUSION: For fetuses with WHS, the most common prenatal ultrasound phenotype was FGR. A region between 1.32 Mb to 1.74 Mb from the telomere on chromosome 4p16.3 is critical for WHS-associated FGR, for which TACC3 and SLBP are the candidate genes.


Assuntos
Cromossomos Humanos Par 3 , Retardo do Crescimento Fetal , Síndrome de Wolf-Hirschhorn , Proteínas de Transporte , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Nucleares/genética , Fenótipo , Gravidez , Síndrome de Wolf-Hirschhorn/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética
7.
Eur J Paediatr Neurol ; 27: 25-29, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32553920

RESUMO

Among 1339 unrelated cases accrued by the Italian National Registry for facioscapulohumeral muscular dystrophy (FSHD), we found three unrelated cases who presented signs of Williams-Beuren Syndrome (WBS) in early childhood and later developed FSHD. All three cases carry the molecular defects associated with the two disorders. The rarity of WBS and FSHD, 1 in 7500 and 1 in 20,000 respectively, makes a random association of the two diseases unlikely. These cases open novel and unexpected interpretation of genetic findings. The nonrandom association of both FSHD and WBS points at a gene co-expression network providing hints for the identification of modules and functionally enriched pathways in the two conditions.


Assuntos
Cromossomos Humanos Par 4/genética , Distrofia Muscular Facioescapuloumeral/genética , Síndrome de Williams/genética , Adolescente , Alelos , Criança , Pré-Escolar , Transtornos Cromossômicos/genética , Deleção de Genes , Humanos , Lactente , Itália , Masculino
8.
Cytogenet Genome Res ; 160(6): 321-328, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32535594

RESUMO

Balanced chromosomal rearrangements are usually associated with a normal phenotype, although in some individuals, phenotypic alterations are observed. In these patients, molecular characterization of the breakpoints can reveal the pathogenic mechanism, providing the annotation of disease-associated loci and a better genotype-phenotype correlation. In this study, we describe a patient with a balanced reciprocal translocation between 4q27 and 7p22 associated with neurodevelopmental delay. We performed cytogenetic evaluation, next-generation sequencing of microdissected derivative chromosomes, and Sanger sequencing of the junction points to define the translocation's breakpoints at base pair resolution. We found that the PCDH10 and TNRC18 genes were disrupted by the breakpoints at chromosomes 4 and 7, respectively, with the formation of chimeric genes at the junction points. Gene expression studies in the patient's peripheral blood showed reduced expression of TNRC18, a gene with unknown function and clinical significance. PCDH10 plays a role in the development of the nervous system and might be involved with the patient's neurodevelopmental delay. In this study, the full molecular characterization of the junction points was shown as an efficient tool for fine breakpoint mapping in balanced translocations in order to unmask gene disruptions and investigate the potential pathogenic role of the disrupted genes.


Assuntos
Caderinas/genética , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 7/genética , Transtornos do Neurodesenvolvimento/genética , Translocação Genética/genética , Adulto , Sequência de Bases , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Transtornos do Neurodesenvolvimento/psicologia
9.
Neurology ; 94(23): e2441-e2447, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32467133

RESUMO

OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2. METHODS: Clinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies. RESULTS: A homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression. CONCLUSION: LRIF1 is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate DUX4 expression in skeletal muscle.


Assuntos
Proteínas de Ciclo Celular/genética , Distrofia Muscular Facioescapuloumeral/genética , Biópsia , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Cromatina/ultraestrutura , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos Humanos Par 4/genética , Códon sem Sentido , Consanguinidade , Fibroblastos , Mutação da Fase de Leitura , Duplicação Gênica , Regulação da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/patologia , Linhagem , Isoformas de Proteínas/genética , Sequências Repetitivas de Ácido Nucleico
10.
Cancer Genet ; 243: 48-51, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32272434

RESUMO

Traditional cytogenetic testing methodologies, including conventional chromosome analysis and fluorescence in situ hybridization (FISH), are invaluable for the detection or recurrent genetic abnormalities in various hematologic malignancies. However, technological advances, including a novel next-generation sequencing technique termed mate-pair sequencing (MPseq), continue to revolutionize the field of cytogenetics by enabling the characterization of structural variants at a significantly higher resolution compared to traditional methodologies. To illustrate the power of MPseq, we present a 27-year-old male diagnosed with chronic myeloid leukemia in myeloid blast crisis with multiple chromosomal abnormalities observed in all 20 metaphases from a peripheral blood specimen, including t(9;22)(q34;q11.2) and t(4;11)(q12;p15). Suspicious of a novel NUP98/PDGFRA fusion [t(4;11)(q12;p15)], break-apart FISH probe sets for the PDGFRA (4q12) and NUP98 (11p15.4) gene regions were performed and were both positive in approximately 86% of 200 interphase nuclei. However, subsequent MPseq testing revealed breakpoints located within the NUP98 gene and within an intergenic region (4q12) located between the CHIC2 and PDGFRA genes, indicating this 4;11 translocation does not result in the predicted NUP98/PDGFRA gene fusion as inferred from FISH and conventional chromosome results. This case demonstrates the clinical utility of MPseq, particularly for characterizing novel gene fusion events which may ultimately identify a false-positive FISH result.


Assuntos
Crise Blástica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Fusão Oncogênica/isolamento & purificação , Adulto , Crise Blástica/diagnóstico , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 9/genética , Análise Citogenética , Progressão da Doença , Reações Falso-Positivas , Humanos , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
11.
Nat Commun ; 11(1): 1238, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144264

RESUMO

An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin ß-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Cromossomos Humanos Par 4/genética , Metilação de DNA , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sistema y+ de Transporte de Aminoácidos/genética , Austrália , Estudos de Casos e Controles , Ilhas de CpG/genética , Regulação para Baixo , Epigenômica/métodos , Feminino , Glutationa/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Nova Zelândia , Doença de Parkinson/sangue , Doença de Parkinson/patologia
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 150-152, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034742

RESUMO

OBJECTIVE: To identify pathological mutation of D4Z4 in a child with facioscapulohumeral muscular dystrophy (FSHD) presented initially as mental retardation. METHODS: Wechsler Intelligence Scale for Children Revised in China (WISC-IV) was used to assess the patient's IQ. Other clinical data was also collected. With genomic DNA extracted from peripheral blood samples, the child and his parents were subjected to medical exome sequencing and copy number variation analysis by next generation sequencing (NGS). The D4Z4 repeats and their origin source were determined by molecular combing. RESULTS: By the WISC-IV test, the child was found to have a total IQ of 41, with a speech comprehension IQ of 45, and perceptual inference index IQ of 52. No pathological mutation was detected by NGS. By molecular combing method, the child was found to carry a D4Z4 spanning 5.2 kb with a copy number of 2. Analysis of his parents indicate that the mutation was de novo. CONCLUSION: The D4Z4 copy number variation may account for the FSHD and mental retardation in the child. The molecular combing method can be used to identify the number of repeat units and facilitate the diagnosis of FSHD.


Assuntos
Deficiência Intelectual , Distrofia Muscular Facioescapuloumeral , Criança , China , Cromossomos Humanos Par 4 , Variações do Número de Cópias de DNA , Humanos , Deficiência Intelectual/genética , Distrofia Muscular Facioescapuloumeral/genética , Mutação
14.
BMC Res Notes ; 13(1): 65, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041645

RESUMO

OBJECTIVE: Alpha-thalassemia is a genetic disorder characterized by deletions of one or more α globin genes that result in deficient of α globin chains reducing haemoglobin concentration. The study aimed to screen 97 patients with microcytosis and hypochromasia for the 3.7 and 4.2 alpha thalassemia deletion mutations. RESULTS: Out of 97 patients screened, only 7 were carriers for the 3.7 deletion and all patients were negative for the 4.2 deletion. The 3.7 deletion was found in Foor, Hawsa and Rezagat Sudanese tribes. In the carriers of the 3.7 deletion, Red Blood Cells and Haematocrit were significantly increased. The Red Blood Cells were 7.23 ± 0.78 × 1012/L in adult males and 7.21 ± 0.67 × 1012/L in adult females while in children were 5.07 ± 0.87 × 1012/L. The mean cell volume and mean cell haemoglobin were significantly decreased, but the mean cell haemoglobin concentration slightly decreased. Haemoglobin levels didn't revealed statistically significant decrease in adult males (11.7 ± 0.57 g/dL) and adult females (11.25 ± 0.64 g/dL), while in children were (11.6 ± 2.95 g/dL). Haemoglobin electrophoresis revealed two patients of the 3.7 and 4.2 negative were carriers for ß-thalassemia. The study concluded that α3.7 deletion has frequency of 0.07 in Sudanese with hypochromasia and microcytosis.


Assuntos
Anemia Hipocrômica/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 4/genética , Testes Genéticos , Talassemia alfa/diagnóstico , Talassemia alfa/genética , Adolescente , Adulto , Anemia Hipocrômica/epidemiologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Deleção de Sequência , Sudão/epidemiologia , Adulto Jovem , Talassemia alfa/epidemiologia
15.
Int J Cancer ; 146(5): 1219-1229, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31087647

RESUMO

We previously identified a novel breast cancer susceptibility variant on chromosome 4q31.22 locus (rs1429142) conferring risk among women of European ancestry. Here, we report replication of findings, validation of the variant in diverse populations and fine-mapping of the associated locus in Caucasian population. The SNP rs1429142 (C/T, minor allele frequency 18%) showed association for the overall breast cancer risk in Stages 1-4 (n = 4,331 cases/4271 controls; p = 4.35 × 10-8 ; odds ratio, ORC-allele ,1.25), and an elevated risk among premenopausal women (n = 1,503 cases/4271 controls; p = 5.81 × 10-10 ; ORC-allele 1.40) in European populations. SNP rs1429142 was associated with premenopausal breast cancer risk in women of African (T/C; p-value 1.45 × 10-02 ; ORC-allele 1.2) but not from Chinese ancestry. Fine-mapping of the locus revealed several potential causal variants which are present within a single association signal, revealed from the conditional regression analysis. Functional annotation of the potential causal variants revealed three putative SNPs rs1366691, rs1429139 and rs7667633 with active enhancer functions inferred based on histone marks, DNase hypersensitive sites in breast cell line data. These putative variants were bound by transcription factors (C-FOS, STAT1/3 and POL2/3) with known roles in inflammatory pathways. Furthermore, Hi-C data revealed several short-range interactions in the fine-mapped locus harboring the putative variants. The fine mapped locus was predicted to be within a single topologically associated domain, potentially facilitating enhancer-promoter interactions possibly leading to the regulation of nearby genes.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 4/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Pré-Menopausa , Adulto , Grupo com Ancestrais do Continente Africano/genética , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Alberta/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Conjuntos de Dados como Assunto , Elementos Facilitadores Genéticos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Regiões Promotoras Genéticas/genética , Adulto Jovem
16.
Fetal Diagn Ther ; 47(2): 98-103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31167209

RESUMO

BACKGROUND: The "double bubble" sign is an ultrasonographic finding that commonly represents duodenal atresia and is associated with trisomy 21. OBJECTIVES: We sought to evaluate the positive predictive value of a prenatally identified double bubble sign for duodenal atresia and the genetic etiologies associated with it. METHODS: We examined a retrospective cohort with prenatal double bubble sign between January 1, 2008, and June 30, 2017. Postnatal diagnoses were determined by review of operative reports and additional postnatal evaluation including cytogenetic analysis, molecular analysis, and/or clinical genetic evaluation. RESULTS: All live births at our institution with a prenatal double bubble sign had confirmed duodenal atresia. Additional anatomic anomalies and/or genetic abnormalities were identified in 62% of cases. Out of 21 cases, 6 had trisomy 21. Of the remaining 15 cases, 8 were nonisolated duodenal atresia, 3 of which had a heterotaxy syndrome. In the 7 isolated cases, 1 likely pathogenic chromosomal microdeletion was identified. CONCLUSIONS: Prenatal double bubble sign is a reliable predictor of duodenal atresia. In addition to trisomy 21, heterotaxy may be encountered. ZIC3 mutations as well as microdeletion of 4q22.3 may be underlying genetic etiologies to be considered in the diagnostic evaluation of a prenatal double bubble sign.


Assuntos
Obstrução Duodenal/diagnóstico por imagem , Atresia Intestinal/diagnóstico por imagem , Ultrassonografia Pré-Natal , Deleção Cromossômica , Cromossomos Humanos Par 4 , Síndrome de Down/genética , Obstrução Duodenal/genética , Predisposição Genética para Doença , Idade Gestacional , Síndrome de Heterotaxia/genética , Humanos , Atresia Intestinal/genética , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco
17.
Dig Dis Sci ; 65(5): 1348-1354, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31584135

RESUMO

BACKGROUND: A recent study reported a novel long non-coding RNA (lncRNA) E2F-mediated cell proliferation enhancing lncRNA (EPEL, human chromosome 4, intergenic region) plays an oncogenic role in lung cancer. AIMS: We aimed to investigate the role of lncRNA EPEL in gastric cancer. METHODS: Gene expression was analyzed by RT-qPCR and western blot. Survival analysis was performed by comparing survival curves. Cell proliferation, migration, and invasion were analyzed by CCK-8 and Transwell assays. RESULTS: We found that lncRNA EPEL and Runt-related transcription factor 2 (RUNX2) were both upregulated in gastric cancer. EPEL and RUNX2 were positively correlated in tumor. Patients with high expression level of lncRNA EPEL showed poor survival. LncRNA EPEL and RUNX2 overexpression promoted, while lncRNA EPEL siRNA silencing inhibited the migration, proliferation, and invasion of gastric cancers. In addition, RUNX2 overexpression completely rescued the inhibited cancer cell migration, proliferation, and invasion caused by lncRNA EPEL siRNA silencing. Consistently, EPEL overexpression resulted in upregulated RUNX2 expression, while RUNX2 overexpression did not affect lncRNA EPEL expression. CONCLUSIONS: Therefore, lncRNA EPEL may regulate cancer cell behaviors and affect prognosis of gastric cancer by interacting with RUNX2.


Assuntos
Proliferação de Células/genética , Subunidade alfa 1 de Fator de Ligação ao Core/fisiologia , Fatores de Transcrição E2F/genética , RNA Longo não Codificante/fisiologia , Neoplasias Gástricas/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Cromossomos Humanos Par 4/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/mortalidade
18.
Leukemia ; 34(2): 358-368, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31462731

RESUMO

Sole trisomies of chromosomes 4, 8, 11, 13 and 21 account for 89-95% of all sole trisomies in adult AML patients. We analyzed clinical and molecular characteristics of 138 de novo AML patients with sole +4, +8, +11, +13 or +21, and compared them with AML patients with those trisomies occurring in addition to other chromosome abnormalities (non-sole trisomy) and with cytogenetically normal AML (CN-AML) patients. Mutations in methylation-related genes were most commonly observed within each sole trisomy group (+4, 55%; +8, 58%; +11, 71%; +13, 71%; +21, 75% of patients). Patients with sole trisomies, excluding +4, also had frequent mutations in spliceosome genes (+8, 43%; +11, 65%; +13, 65%; +21, 45% of patients). In contrast, +4 patients frequently had mutations in transcription factor genes (44%) and NPM1 (36%). While 48% of patients with sole trisomies harbored mutations in a spliceosome gene, spliceosome mutations were observed in only 24% of non-sole trisomy (n = 131, P < 0.001) and 19% of CN-AML patients (n = 716, P < 0.001). Our data suggest that mutations affecting methylation-related genes are a molecular hallmark of sole trisomies. Mutations in spliceosome genes were also commonly observed in many sole trisomy patients and represent a novel finding in this cytogenetic subgroup.


Assuntos
Leucemia Mieloide Aguda/genética , Trissomia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Medicine (Baltimore) ; 98(50): e18268, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852098

RESUMO

RATIONALE: Wolf-Hirschhorn Syndrome (WHS) is a rare disorder caused by the loss of the distal part of the short arm of chromosome 4, and has various phenotypes depending on the deletion size. Although many articles report on urinary tract malformations or ophthalmologic abnormalities, there are few descriptions of the skeletal anomalies. This is an extremely rare case of cervical dysplasia in WHS. PATIENT CONCERNS: A 24-year-old pregnant woman was transferred to our hospital at 21 gestational weeks for intrauterine growth retardation and oligohydramnios and decided to preserve the pregnancy after evaluation. A female was born at full term by normal vaginal delivery, weighing 1791 g. The patient was suspected to have congenital dysplasia of the cervical vertebrae on the routine newborn chest radiograph, and cervical spine magnetic resonance imaging revealed nonossification of the C3 and C4 vertebral bodies. DIAGNOSIS: The newborn had the "Greek warrior helmet" face typical of WHS. A deletion was detected in the distal portion of the short arm of chromosome 4 (p 16.3) by fluorescence in situ hybridization analysis. INTERVENTIONS: She was hospitalized for nutritional management and congenital anomaly evaluation for a month before being discharged with rehabilitation and antiepileptic drugs. OUTCOMES: The patient has been readmitted with seizure attacks 5 times to date. At one year of age, she still shows severe head lag and feeding problems. Her last weight was below the 3rd centile. LESSONS: Although cervical dysplasia is a rarely reported morphology in WHS, it may provide artefacts for diagnosing WHS as cervical anomalies, unlike facial anomalies or developmental delays, are seldom found in congenital disease.


Assuntos
Doenças do Desenvolvimento Ósseo/etiologia , Vértebras Cervicais/patologia , Cromossomos Humanos Par 4/genética , Síndrome de Wolf-Hirschhorn/complicações , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Feminino , Humanos , Recém-Nascido , Cariotipagem , Imagem por Ressonância Magnética , Fenótipo , Gravidez , Síndrome de Wolf-Hirschhorn/diagnóstico , Síndrome de Wolf-Hirschhorn/genética , Adulto Jovem
20.
J Stud Alcohol Drugs ; 80(6): 585-593, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31790348

RESUMO

OBJECTIVE: Epidemiological estimates suggest that nearly half of individuals diagnosed with alcohol use disorder will be diagnosed with another mental health disorder, with strong associations involving other externalizing disorders. Molecular genetic studies investigating the relation between alcohol use disorder and externalizing behaviors (e.g., antisocial behavior) have focused on a cluster of chromosome 4 γ-aminobutyric acid (GABA) receptor genes (GABRG1-A2-A4-B1) but have generated varying results. METHOD: The current study examined associations between common and rare variation in this region with alcohol use disorder and antisocial behavior using genetic sequencing data. Specifically, the University of California at San Francisco Family Alcoholism Sample (n = 1,610; 62% female) was used to conduct common and rare variant association tests in the GABRG1-A2-A4-B1 cluster with DSM-5 alcohol use disorder symptom counts, antisocial behavior, and a product term representing their interaction. RESULTS: Gene-based analyses of rare variation resulted in a significant association between rare GABRA2 variation and the interaction term. Single-variant analysis yielded only nominally significant associations. The strongest association for alcohol use disorder (rs3756007) was located in GABRA2, the strongest association for antisocial behavior (rs11941860) was located in GABRG1, and the interaction term yielded top associations in GABRA2 (rs2119183) and the intergenic region between GABRA2 and GABRG1 (rs536599). Common and rare variant associations for the interaction remained similar when covarying for the effects of the other type of variation, suggesting that the significant rare variant signal is independent of common variant contributions. CONCLUSIONS: The present study suggests that both rare and common variant associations in GABRA2 confer risk for alcohol use disorder and antisocial behaviors, indicating a potential liability toward externalizing behavior more broadly.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Transtorno da Personalidade Antissocial/genética , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Receptores de GABA-A/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 4/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
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