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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1015-1018, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598949

RESUMO

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for a family affected with Duchenne muscular dystrophy (DMD). METHODS: Multiplex ligation dependent probe amplification (MLPA) was used to detect potential deletion and duplication of the Dystrophin gene. Haplotype analysis was performed using five short tandem repeat polymorphism loci (3'-STR, 5'-STR, 45-STR, 49-STR, 50-STR of the DMD gene. RESULTS: A same deletional mutation (exons 51-55) of the DMD gene was detected in two brothers but not in their mother. The patients and fetus have inherited different haplotypes of the Dystrophin gene from their mother, suggesting that the fetus was unaffected. CONCLUSION: The mother was very likely to harbor germline mosaicism for the Dystrophin gene variant. Genetic testing of peripheral blood samples cannot rule out germline mosaicism in the mother. Prenatal diagnosis should be provided for subsequent pregnancies in this family.


Assuntos
Distrofina/genética , Deleção de Genes , Mutação em Linhagem Germinativa , Mosaicismo , Distrofia Muscular de Duchenne/genética , Éxons , Feminino , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal
2.
Medicine (Baltimore) ; 98(39): e17372, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574885

RESUMO

INTRODUCTION: Cyclic neutropenia (CyN) is a rare hematological disease, and patients with CyN often experience an early onset of severe periodontitis and are forced to undergo tooth extraction. Here, we report a case of a patient with CyN who showed different periodicity and oscillations of neutrophil count compared with her mother, despite sharing the same novel genetic mutation. PATIENT CONCERNS: A 17-year-old Japanese girl who had been diagnosed with CyN shortly after birth presented to our hospital with a complaint of mobility of her teeth and gingivitis. Upon presentation, an intraoral examination was performed and revealed redness and swelling of the marginal and attached gingiva. Radiographs revealed extreme resorption of the alveolar bone and apical lesions in her mandibular lateral incisors. The patient's hematologic data demonstrated a lack of blood neutrophils (0/µL). The patient had no history of dental extraction, and her mother also had a history of CyN. DIAGNOSES: The patient was diagnosed with severe periodontitis that was associated with CyN. Gene testing showed a novel heterozygous mutation in exon 4 of the ELANE gene (c.538delC, p.Leu180Ser fsX11). INTERVENTIONS: Based on the clinical findings, we planned to extract the patient's mandibular lateral incisors. Although the tooth extraction was scheduled considering the cyclic variation in neutrophil count, the patient's neutrophil count was 0/µL on the day before the planned extraction. Therefore, granulocyte-colony stimulating factor (G-CSF) was administered to increase the patient's neutrophil count. On the day of the patient's admission for the tooth extraction, she presented with fever (body temperature, 38.5°C), tonsillitis, and stomatitis. The extraction was subsequently delayed, and the patient was administered antibiotics and G-CSF for 4 days. At this time, the neutrophil count increased to 750/µL, and the tooth extraction was carried out safely. OUTCOMES: The postoperative course was uneventful, and the healing process at the extraction site was excellent. CONCLUSION: There is a possibility that the periodicity and oscillations of neutrophil count may change with growth in patients with CyN. Therefore, it is important to frequently examine and treat patients with fluctuating neutrophil levels for the management of invasive dental treatment in patients with CyN.


Assuntos
Elastase de Leucócito/genética , Neutropenia/genética , Periodontite/genética , Periodontite/cirurgia , Extração Dentária/efeitos adversos , Adolescente , Éxons , Feminino , Humanos , Contagem de Leucócitos , Mutação , Neutropenia/sangue , Neutropenia/complicações , Neutrófilos , Periodontite/sangue
3.
Hum Genet ; 138(10): 1183-1200, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471722

RESUMO

The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Genes Recessivos , Predisposição Genética para Doença , Mutação , Fenótipo , Transaminases/genética , Adolescente , Alelos , Substituição de Aminoácidos , Deficiências do Desenvolvimento/metabolismo , Ativação Enzimática , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Genética Populacional , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Moleculares , Linhagem , Conformação Proteica , Sítios de Splice de RNA , Análise de Sequência de DNA , Relação Estrutura-Atividade , Transaminases/química , Transaminases/metabolismo
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 877-881, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515780

RESUMO

OBJECTIVE: To identify pathogenic variants in 5 sporadic patients and two Chinese pedigrees affected with 17-hydroxylase deficiency (17-OHD). METHODS: Peripheral blood samples were collected with informed consent. Variants of CYP17A1 gene were screened by PCR and Sanger sequencing. Suspected mutations were validated in other members of the pedigrees. RESULTS: Gene sequencing has identified a homozygous c.985_987delTACinsAA (Y329Kfs) mutation in exon 6 of the CYP17A1 gene in 4 patients and the sister of case 3. Case 1 was found to harbor compound heterozygous mutations c.1459_1467del9 (p.D487_F489del) and c.1244-3C>A. The parents and brother of cases 2 and 5 were heterozygous carriers of a c.985_987delTACinsAA(Y329Kfs) mutation. CONCLUSION: Mutations of the CYP17A1 gene probably underlie the pathogenesis of 17-OHD, for which c.985_987delTACinsAA(Y329Kfs) is the most common. The c.1244-3C>A is a novel mutation. Above results have facilitated genetic counseling for the affected families.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Esteroide 17-alfa-Hidroxilase/genética , Éxons , Feminino , Humanos , Masculino , Mutação , Linhagem
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 905-909, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515787

RESUMO

OBJECTIVE: To detect mutation of LBR gene in a pedigree affected with Pelger-Huёt anomaly (PHA) and to explore its clinical characteristics. METHODS: Genomic DNA was extracted from the pedigree and healthy controls. The 14 exons of the LBR gene were subjected to PCR amplification and Sanger sequencing. Suspected mutations were verified in other family members and 100 healthy controls. Polyphen-2 and SIFT software were used to predict the effect of the mutation, and Swiss-model software was used to simulate the protein structure. RESULTS: Three patients were found to carry a c.893G>A mutation in exon 8 of the LBR gene, which resulted in substitution of the 298th amino acid residue glycine by glutamic acid (p.Gly298Glu). The same mutation was not found in healthy family members and 100 healthy controls. The mutation was predicted to be damaging. Bioinformatic simulation showed the mutation has altered the 3D structure of the LBR protein. CONCLUSION: The c.893G>A (p.Gly298Glu) mutation in the LBR gene probably underlies the PHA in this pedigree and has enriched the spectrum of LBR gene mutations.


Assuntos
Anomalia de Pelger-Huët/genética , Receptores Citoplasmáticos e Nucleares/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Éxons , Humanos , Mutação , Linhagem , Reação em Cadeia da Polimerase
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 914-917, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515789

RESUMO

OBJECTIVE: To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase. METHODS: Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product. RESULTS: High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c.4550T>G in exon 47 (inherited from his mother) and c.199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother. CONCLUSION: The compound heterozygous c.4550T>G and c.199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.


Assuntos
Colágeno Tipo IV/genética , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Criança , Éxons , Feminino , Humanos , Masculino , Mutação , Linhagem , Sequenciamento Completo do Exoma
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 930-934, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515793

RESUMO

OBJECTIVE: To detect potential mutations of HEXB gene in an infant with Sandhoff disease (SD). METHODS: Genomic DNA was extracted from peripheral blood sample of the infant. All coding exons (exons 1 to 14) and splicing sites of the HEXB gene were subjected to PCR amplification and direct sequencing.PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. PubMed BLAST CD-search was performed to identify functional domains destroyed by thecandidate mutations. Impact of the mutations was analyzed with software including PolyPhen-2, Mutation Taster and SIFT. Whole-exome sequencing was carried out to identify additional mutations. RESULTS: The infant was found to carry compound heterozygous mutations c.1652G>A(p.Cys551Tyr) and c.1389C>G (p.Tyr463*) of the HEXB gene. The c.1389C>G (p.Tyr463*) mutation may lead to destruction of two functional domains in ß subunit of the Hex protein. The c.1652G>A(p.Cys551Tyr) mutation, unreported previously,was predicted to be probably damaging by Bioinformatic analysis. CONCLUSION: Compound heterozygous mutations c.1652G>A(p.Cys551Tyr) and c.1389C>G (p.Tyr463*) in the HEXB gene probably underlie the disease in this patient.


Assuntos
Doença de Sandhoff/genética , Cadeia beta da beta-Hexosaminidase/genética , Análise Mutacional de DNA , Éxons , Heterozigoto , Humanos , Lactente , Mutação , Reação em Cadeia da Polimerase
8.
Gene ; 719: 144075, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31449843

RESUMO

The human L-DOPA decarboxylase (DDC) is a gene that has been in the center of research attention in many laboratories the last decades, due to its major implication in various disorders, including many types of cancer. In the current work, we used in-house developed RACE and high-throughput sequencing approaches, in order to detect and identify novel DDC transcripts. Bioinformatic analysis revealed new alternative splicing events that support the existence of novel DDC transcripts. As a result, a total of 14 DDC splice variants were identified and their expression profile was investigated in a wide panel of human cancer cell lines. From all 14 novel DDC transcripts that were identified, 9 transcripts are predicted to encode new protein isoforms, while the remaining 5 are nonsense-mediated mRNA decay (NMD) candidates. Our results demonstrate that the human DDC gene undergoes complex processing leading to the figuration of multiple mRNA isoforms in cancer cells.


Assuntos
Processamento Alternativo , Descarboxilases de Aminoácido-L-Aromático/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequência de Bases , Linhagem Celular Tumoral , Éxons , Perfilação da Expressão Gênica , Humanos , RNA Mensageiro/genética
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 773-776, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400125

RESUMO

OBJECTIVE: To discuss the value of chromosomal microarray analysis (CMA) for the identification of DMD gene deletions during prenatal diagnosis. METHODS: G-banded karyotyping and CMA were performed on fetuses with ultrasonographic soft markers but no family history for Duchenne/Becker muscular dystrophy (DMD/BMD). Denaturing high-performance liquid chromatograghy (DHPLC) was used to detect DMD gene mutations in umbilical cord blood and peripheral blood samples from the mothers. RESULTS: For fetus 1, analysis of amniocytes showed a normal karyotype, while CMA detected a 119 kb deletion at Xp21.1 (32 565 489 - 32 681 461), which encompassed exons 10 to 16 of the DMD gene. The result was confirmed by DHPLC analysis. The mother was found to have loss of heterozygosity in the same region. For fetus 2, karyotyping of amniocytes also showed a normal male karyotype, while CMA detected a 254 kb deletion at Xp21.1 (32 104 604 - 32 358 874), which encompassed exons 41 to 44 of the DMD gene. The same deletion was not detected in the mother. DHPLC analysis confirmed the presence of both deletions. CONCLUSION: Two fetuses harboring DMD gene deletions but without a family history were discovered. CMA can improve the efficiency for detecting single gene diseases caused by deletions.


Assuntos
Distrofina/genética , Deleção de Genes , Achados Incidentais , Análise em Microsséries , Distrofia Muscular de Duchenne/genética , Éxons , Feminino , Feto , Humanos , Masculino , Gravidez
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 801-804, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400132

RESUMO

OBJECTIVE: To analyze the phenotype and genetic mutations in a pedigree affected with factor Ⅺ (FⅪ) deficiency. METHODS: Activated partial thromboplastin time (APTT), FⅪ activity (FⅪ:C) and FⅪ antigen (FⅪ:Ag) were determined for the proband and his family members. All exons and exon-intron boundaries of the FⅪ gene of the proband were analyzed by direct sequencing. Suspected mutation was verified in his family members. RESULTS: The proband had APTT of 82.4 s, FⅪ:C of 0.8%, and FⅪ:Ag of <1%. DNA sequencing showed that he has carried c.1033A>T (Lys327X) mutation in exon 10 and c.1325delT (Leu424CysfsX8) mutation in exon 12 of the FⅪ gene. His elder sister, son, daughter, two granddaughters and one grandson were heterozygous carriers of the c.1033A>T mutation, while his older sister and younger brother were heteozygous carriers of the c.1325delT mutation. Analysis using Mutation Taster software showed that both p.Lys327X and p.Leu424CysfsX8 may affect the function of protein and lead to the corresponding disease. CONCLUSION: The novel mutations of Lys327X and Leu424CysfsX8 of the the FⅪ gene probably underlie the pathogenesis of congenital coagulation factor Ⅺ deficiency in this pedigree.


Assuntos
Deficiência do Fator XI/genética , Fator XI/genética , Éxons , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem
11.
BMC Bioinformatics ; 20(1): 436, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438850

RESUMO

BACKGROUND: Creating a scalable computational infrastructure to analyze the wealth of information contained in data repositories is difficult due to significant barriers in organizing, extracting and analyzing relevant data. Shared data science infrastructures like Boag is needed to efficiently process and parse data contained in large data repositories. The main features of Boag are inspired from existing languages for data intensive computing and can easily integrate data from biological data repositories. RESULTS: As a proof of concept, Boa for genomics, Boag, has been implemented to analyze RefSeq's 153,848 annotation (GFF) and assembly (FASTA) file metadata. Boag provides a massive improvement from existing solutions like Python and MongoDB, by utilizing a domain-specific language that uses Hadoop infrastructure for a smaller storage footprint that scales well and requires fewer lines of code. We execute scripts through Boag to answer questions about the genomes in RefSeq. We identify the largest and smallest genomes deposited, explore exon frequencies for assemblies after 2016, identify the most commonly used bacterial genome assembly program, and address how animal genome assemblies have improved since 2016. Boag databases provide a significant reduction in required storage of the raw data and a significant speed up in its ability to query large datasets due to automated parallelization and distribution of Hadoop infrastructure during computations. CONCLUSIONS: In order to keep pace with our ability to produce biological data, innovative methods are required. The Shared Data Science Infrastructure, Boag, provides researchers a greater access to researchers to efficiently explore data in new ways. We demonstrate the potential of a the domain specific language Boag using the RefSeq database to explore how deposited genome assemblies and annotations are changing over time. This is a small example of how Boag could be used with large biological datasets.


Assuntos
Ciência de Dados , Genômica , Disseminação de Informação , Animais , Bases de Dados Factuais , Bases de Dados Genéticas , Éxons/genética , Genoma , Análise de Sequência de DNA , Software
12.
Rinsho Ketsueki ; 60(7): 767-772, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391364

RESUMO

BCR-ABL1 International Scale (IS) measurement is an important technique used to monitor chronic myeloid leukemia (CML) when patients are treated with tyrosine kinase inhibitors. In very rare cases, the BCR-ABL1 IS measurement fails to detect BCR-ABL1 chimeric messages for unknown reasons. Such a situation was also experienced in our study; therefore, molecular analysis of BCR-ABL1 fusion gene was performed. A breakpoint in the ABL1 gene was identified in the middle of the a2 exon, leading to generation of chimeric messages lacking a nucleic acid sequence encoded by this exon (e14a3 chimeric message). The ABL1 a2 exon is critical for quantification of BCR-ABL1 chimeric messages with the measurement scales used in medical laboratories. Absence of this referred nucleic acid sequence was the reason why BCR-ABL1 IS measurement failed to detect the chimeric messages in our study. In the future, such rare cases of CML, with BCR-ABL1 chimeric messages not detected by standard IS measurements, in Japan should be collected and their molecular structures should be analyzed.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Éxons , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética
13.
Gene ; 716: 144036, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31381952

RESUMO

Nebulin is a 770 kDa protein that is localized along the thin filaments of skeletal muscles in vertebrates. It is also present in the striated muscles of Amphioxus, an invertebrate cephalochordate that is phylogenetically close to vertebrates. However, the nebulin of urochordate ascidians or its expression in invertebrate hearts has not been investigated. In this study, we investigated the structure and cardiac expression of the nebulin gene in Ciona intestinalis, a urochordate whose phylogeny lies between cephalochordates and vertebrates. As a result of the gene structure analysis, we found that the Ciona nebulin gene predicted to be 62 kb and consists of 143 exons. The nebulin was expected to consist of a unique N-terminal region, followed by 155 nebulin repeats, another unique region, a Ser-rich region and a C-terminal SH3 domain. Whole-mount in situ hybridization experiments showed that the Ciona nebulin gene was expressed in a variety of muscles, including hearts. However, Western blot analysis using antibody to Ciona nebulin did not detect the presence of full-length nebulin. Alternatively, RT-PCR experiments on samples of Ciona heart detected the expression of nebulette-like and nrap-like isoforms from the Ciona nebulin gene. These results indicate that, similarly to vertebrate hearts, Ciona hearts do not express nebulin, but rather nrap- and nebulette-like isoforms. These results also imply that the nebulin, nebulette and nrap genes in vertebrates were separated from an ancestral invertebrate nebulin gene during vertebrate evolution.


Assuntos
Ciona intestinalis/genética , Família Multigênica , Proteínas Musculares/genética , Miocárdio/metabolismo , Animais , Ciona intestinalis/metabolismo , Evolução Molecular , Éxons , Íntrons , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Domínios Proteicos , RNA Mensageiro/metabolismo
14.
DNA Cell Biol ; 38(10): 1100-1111, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31418589

RESUMO

Members of the Sox gene family play crucial roles during reproduction and development, but their genome-wide identification has not yet been performed in large yellow croaker, Larimichthys crocea. In this study, a total of 26 members of the Sox gene family were identified from the genome of large yellow croaker and classified into seven subgroups based on the conserved HMG-box domain they contain. Among the identified Sox gene family members, eight belonged to the SoxB subgroup (five in B1 and three in B2), four belonged to the SoxC subgroup, four belonged to the SoxD subgroup, six belonged to the SoxE subgroup, three belonged to the SoxF subgroup, and one belonged to the SoxK subgroup. During evolution, members of the SoxE subgroup (Sox8, Sox9, Sox10), Sox1, Sox4, Sox6, and Sox11 evolved into two copies, which may be a result of teleost-specific whole-genome duplication. Sox genes were distributed unevenly across 15 chromosomes. The number of introns in large yellow croaker Sox genes varied from 0 to 14. Results of the expression profile during embryogenesis revealed that most of the members of the Sox gene family had lower expression, except several Sox genes, and expression patterns also differed among each Sox gene group and duplicated gene. This study systematically characterized and analyzed the Sox gene family in large yellow croaker and provided new insights into its function during embryogenesis.


Assuntos
Proteínas de Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Perciformes/genética , Filogenia , Fatores de Transcrição SOXB1/genética , Sequência de Aminoácidos , Animais , Evolução Biológica , Mapeamento Cromossômico , Biologia Computacional , Embrião não Mamífero , Desenvolvimento Embrionário , Éxons , Proteínas de Peixes/classificação , Duplicação Gênica , Íntrons , Família Multigênica , Perciformes/classificação , Isoformas de Proteínas/classificação , Isoformas de Proteínas/genética , Fatores de Transcrição SOXB1/classificação , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
15.
Artigo em Chinês | MEDLINE | ID: mdl-31256520

RESUMO

Objective: To observe the effect of epidermal growth factor receptor tyrosinase inhibitor (EGFR-TKIs) on silica (SiO(2))-induced pulmonary fibrosis in rats, and to explore the role of epidermal growth factor receptor (EGFR) signaling pathway in pulmonary fibrosis. Methods: A rat model of SiO(2) silicosis was established (high, medium and low dose intervention groups, and the model group was infused with silica suspension). The control group was intratracheally injected with the same amount of sterile saline. The rats were intragastrically administered with different concentrations of EGFR-TKIs (13.5 mg/day, 6.75 mg/day, 3.375 mg/day). The model group and the control group were given the same amount of normal saline. Six rats in each group were euthanized on the 3rd, 7th, and 14th days after modeling. HE staining was used to observe the pathological of lung tissue. Masson staining to observe pulmonary fibrosis. Immunohistochemistry (IHC) expression of p-EGFR. Determination of hydroxyproline content by alkaline hydrolysis of the sample, Western Blot was used to detect the contents of TGF-α, Ras, p-Erkl/2, PI-3KCG and Aktl protein in lung tissue. Results: The degree of fibrosis and hydroxyproline content in HE staining and Masson staining decreased with the increase of intervention dose, which was statistically significant (7 d, 14 d). Compared with the model group, the relative expressions of TGF-α, p-Erkl/2 and Aktl protein in lung tissue of each intervention group were statistically significant (P<0.05). The down-regulation of Ras and PI-3KCG protein in the high- and medium-dose intervention group was statistically significant (P<0.05), and there was no significant difference in the low-dose intervention group.Compared with the intervention group, the down-regulation of TGF-α, Ras, and p-Erkl/2 protein in the lung tissue was statistically different in the low-dose group (P<0.05). There was no significant difference between the dose and the medium dose intervention group (P>0.05). PI-3KCG was significantly different only in the high-dose intervention group and the low-dose intervention group on the 7th and 14th day (P<0.05), and there was no difference between the other groups (P>0.05). There was a statistically significant difference in Akt1 between the dose intervention groups (P<0.05). Conclusion: EGFR-TKIs inhibits EGFR-related intracellular tyrosine kinase activity and intracellular phosphorylation, and inhibits the downstream signal transduction pathways of EGFR/PI-3K/AKt and Ras/ERK/MAPK target protein Ras, p-Erkl/2, PI3K, Akt1, thereby alleviating changes in pulmonary fibrosis, this process is dose-dependent, and the high-dose and medium-dose intervention groups have a significant effect.


Assuntos
Silicose , Animais , Receptores ErbB , Éxons , Pulmão , Monofenol Mono-Oxigenase , Inibidores de Proteínas Quinases , Ratos , Ratos Wistar , Dióxido de Silício
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 716-719, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302919

RESUMO

OBJECTIVE: To report on a child with mental retardation caused by SYNGAP1 gene mutation. METHODS: Peripheral blood samples were collected from the proband and her parents. High throughput sequencing (HTS) was employed for screening for potential mutation in the patient. Suspected mutation was validated by Sanger sequencing of the child and her parents. RESULTS: By HTS, a previously unknown mutation [c.1656C>A (p.C552*)] was found in exon 10 of the SYNGAP1 gene in the proband. Sanger sequencing confirmed the heterozygous nature of the mutation and that neither of her parents carried the same mutation. CONCLUSION: The dysmorphism and developmental delay of the child were probably due to the pathogenic mutation of the SYNGAP1 gene. HTS can facilitate elucidation of the genetic etiology with efficiency, which has great significance in the diagnosis, treatment and prognosis of the child.


Assuntos
Deficiência Intelectual/genética , Proteínas Ativadoras de ras GTPase/genética , Criança , Éxons , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 731-733, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302923

RESUMO

OBJECTIVE: To report on a novel weak D type identified in a Chinese individual. METHODS: Peripheral blood sample was collected for a voluntary blood donor with weakened expression of D antigen. Routine serological testing was carried out to determine the D, C, c, E and e antigens of the Rh blood group. A D-screening kit was used to analyze the RhD epitopes. The 10 exons and flanking intronic regions of the RHD gene were sequenced. The zygosity of RHD was determined with a sequence-specific primer PCR method. RESULTS: A novel RHD allele, RHD (1022T>A), was found in the subject with a weak D phenotype. Serological testing of the RhD epitopes has coined with the weak D phenotype. CONCLUSION: A novel weak D allele has been identified in Chinese population.


Assuntos
Alelos , Sistema do Grupo Sanguíneo Rh-Hr/genética , Grupo com Ancestrais do Continente Asiático , China , Éxons , Genótipo , Humanos , Íntrons
18.
Psychiatr Danub ; 31(2): 263-268, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291235

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a complex stress related disorder, that follows a severe traumatic experience, characterized with an intense sense of terror, fear, and helplessness. The aim of this study is to identify associations of genetic variations within candidate genes DRD2 and DRD4 with various PTSD related phenotypes. PTSD lifetime and PTSD current subjects were analyzed separately, each of them were analyzed in a Case/Control design, as well as regarding BSI and CAPS within cases only. SUBJECTS AND METHODS: 719 (487 male, 232 female) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Hercegovina, Kosovo and Croatia were included in the study. Sociodemographic questionnaire, Clinician Administered PTSD Scale (CAPS) and the Brief Symptom Inventory (BSI) were used to collect clinical data. RESULTS: The DRD2 rs1800497 variant and a variable number tandem repeat (VNTR) located in exon three of DRD4 were investigated for association with PTSD. In case control analyses we did not identify any significant associations. Within the PTSD current patients, we identified an association of DRD2 rs1800497 with BSI in the genotypic and the recessive model with the T allele as the risk allele. CONCLUSION: Our findings suggest that rs1800497 of DRD2 gene is involved in pathogenesis of PTSD.


Assuntos
Repetições Minissatélites , Polimorfismo Genético , Receptores de Dopamina D2/genética , Receptores de Dopamina D4/genética , Transtornos de Estresse Pós-Traumáticos/genética , Conflitos Armados/psicologia , Bósnia e Herzegóvina , Croácia , Éxons/genética , Feminino , Humanos , Kosovo , Masculino , Pessoa de Meia-Idade
19.
Yi Chuan ; 41(6): 509-523, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31257199

RESUMO

UDP-glucuronosyltransferases (UGTs) are an important family of phase 2 drug-metabolizing enzymes that catalyze the glucuronidation of numerous endogenous or exogenous small compounds. The aberrant expression of UGT isoforms causes many diseases, such as hyperbilirubinemia and affect drug efficacy or toxicity. Understanding mechanisms of UGT gene regulation will provide scientific foundations for disease prevention and personalized or precision medicine. Vertebrate UGT family genes can be divided into UGT1 and UGT2 subfamilies. Similar to the protocadherin, immunoglobulin, and T-cell receptor gene clusters and different from the UGT2 gene cluster, the UGT1 gene cluster is organized into variable and constant regions. The UGT1 variable region contains a tandem array of variable exons, each of which can be alternatively spliced to a single set of 4 downstream constant exons, generating at least nine UGT1 mRNAs that could be translated into different UGT1 glucuronyltransferase isoforms. Our previous work reveals that the relative orientations and locations of CTCF binding sites play a key role in the three-dimensional organization of the mammalian genomes in cell nuclei. Thus in order to study the transcriptional mechanisms of UGT1 gene cluster, the distributions and orientations of CTCF binding sites (CBSs) are analyzed and compared between human and mouse UGT1 gene clusters. We find that the CBSs in the UGT1 gene cluster are not conserved between human and mouse species. We show that CTCF and cohesin regulate the transcription of the UGT1 gene cluster by knocking down the CTCF or the cohesin subunit SMC3 in the human A549 cell line. By using CRISPR DNA-fragment editing, we deleted and inverted hCBS1. By RNA-seq experiments, we find that hCBS1 deletion results in a significant decrease of levels of the UGT1A6, UGT1A7, and UGT1A9 gene expression and that hCBS1 inversion results in a significant decrease of levels of the UGT1A7 gene expression. Our data suggest that the CTCF binding site hCBS1 plays an important regulatory role in the regulation of UGT1 gene expression, providing an experimental basis for further mechanistic studies of the 3D genome regulation of the UGT1 gene cluster.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Regulação da Expressão Gênica , Glucuronosiltransferase/genética , Família Multigênica , Animais , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Éxons , Humanos , Camundongos , RNA Mensageiro
20.
Gan To Kagaku Ryoho ; 46(7): 1097-1102, 2019 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-31296810

RESUMO

Lynch syndrome is one of the most common inherited predisposition syndromes which demonstrated autosomal dominant manner and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. Lynch syndrome is caused by germline pathogenic variants in any of 4 DNA mismatch repair(MMR)genes MLH1, MSH2, MSH6 or PMS2 and rarely in the non-MMR gene EPCAM, in which deletion of its last exon induce epigenetic silencing of MSH2. Resent advances have been occurred in our understanding of the epidemiology of this disease and the advent of multigene panel tests brought more understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome and these advances have important implications of prevention, risk-reduction and immunotherapy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias do Endométrio , Reparo de Erro de Pareamento de DNA , Éxons , Feminino , Predisposição Genética para Doença , Humanos
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