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[PMID]: 28456808 [Au] Autor: Batista RL; Rodrigues AS; Nishi MY; Feitosa ACR; Gomes NLRA; Junior JAF; Domenice S; Costa EMF; de Mendonça BB [Ad] Endereço: Unidade de Endocrinologia do Desenvolvimento, Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas, Laboratório de Hormônios e Genética Molecular (LIM/42), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil. [Ti] Título: Heterozygous Nonsense Mutation in the Androgen Receptor Gene Associated with Partial Androgen Insensitivity Syndrome in an Individual with 47,XXY Karyotype. [So] Source: Sex Dev;11(2):78-81, 2017. [Is] ISSN: 1661-5433 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: There are only 2 patients with 47,XXY karyotype and androgen receptor (AR) gene mutation reported in the literature, and both are diagnosed as complete androgen insensitivity syndrome (CAIS). We report a 22-year-old female with 47,XXY karyotype and atypical external genitalia. Sequencing of AR revealed the heterozygous p.Asn849Lys*32 mutation, and extensive X chromosome microsatellite analysis showed homozygosity for Xp and heterozygosity for Xq, suggesting partial X maternal isodisomy. Partial androgen insensitivity syndrome (PAIS) developed in this case, probably because of the presence of the heterozygous AR mutation and random X- inactivation of the healthy allele. This is the first report of a female patient with 47,XXY karyotype and PAIS phenotype. [Mh] Termos MeSH primário: Síndrome de Resistência a Andrógenos/genética Códon sem Sentido/genética Predisposição Genética para Doença Cariótipo Mutação/genética Receptores Androgênicos/genética [Mh] Termos MeSH secundário: Sequência de Bases Éxons/genética Feminino Heterozigoto Homozigoto Seres Humanos Masculino Repetições de Microssatélites/genética Adulto Jovem [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE [Nm] Nome de substância: 0 (AR protein, human); 0 (Codon, Nonsense); 0 (Receptors, Androgen) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170501 [St] Status: MEDLINE [do] DOI: 10.1159/000468957

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[PMID]: 29442031 [Au] Autor: Peng Y; Xu B; Tang J; Wan Z; Sun H; Wang G; Zhu YS [Ti] Título: Analysis of ABCG2 methylation in stool samples of Chinese healthy males by pyrosequencing. [So] Source: Pharmazie;71(8):447-454, 2016 08 01. [Is] ISSN: 0031-7144 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: ABCG2, an efflux pump protein-BCRP coding gene, is involved in the acquisition of chemotherapeutic drug resistance. In recent years, the epigenetic regulation of ABCG2, such as DNA methylation, has become a research hotspot and been attracting widespread attention. Methylation Special PCR (MSP) has been the mainly used method for gene methylation detection for a long time. With the development of pyrosequencing (PSQ) instrument and the convenience, simpleness, and economical benefit it brings, it will become the mainstream method for gene methylation detection in the near future. This study aims to establish a pyrosequencing method for detecting the methylation sites on ABCG2 gene promoter up-stream region, the promoter region and the first exon region, and to detect the methylation level of each site in stool samples, respectively. Thus, it cannot only lay the methodological foundation for the study of BCRP-mediated multi-drug resistance mechanisms in tumor cells, but also can give knowledge of ABCG2 methylation distribution in the intestine of Chinese healthy males by detecting the ABCG2 methylation levels in stool samples as the exfoliated intestinal epithelial cells constantly shed into the stool. [Mh] Termos MeSH primário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética Fezes/química Proteínas de Neoplasias/genética Análise de Sequência de Proteína/métodos [Mh] Termos MeSH secundário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo Adulto Grupo com Ancestrais do Continente Asiático Ilhas de CpG/genética Metilação de DNA Epigênese Genética Éxons Voluntários Saudáveis Seres Humanos Masculino Proteínas de Neoplasias/metabolismo Regiões Promotoras Genéticas [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (ABCG2 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (Neoplasm Proteins) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180307 [Lr] Data última revisão: 180307 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180215 [St] Status: MEDLINE [do] DOI: 10.1691/ph.2016.6559

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[PMID]: 29434199 [Au] Autor: Hayashi T; Ozaki H; Sasagawa Y; Umeda M; Danno H; Nikaido I [Ad] Endereço: Bioinformatics Research Unit, Advanced Center for Computing and Communication, RIKEN, 2-1 Hirosawa Wako, Saitama, 351-0198, Japan. [Ti] Título: Single-cell full-length total RNA sequencing uncovers dynamics of recursive splicing and enhancer RNAs. [So] Source: Nat Commun;9(1):619, 2018 02 12. [Is] ISSN: 2041-1723 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Total RNA sequencing has been used to reveal poly(A) and non-poly(A) RNA expression, RNA processing and enhancer activity. To date, no method for full-length total RNA sequencing of single cells has been developed despite the potential of this technology for single-cell biology. Here we describe random displacement amplification sequencing (RamDA-seq), the first full-length total RNA-sequencing method for single cells. Compared with other methods, RamDA-seq shows high sensitivity to non-poly(A) RNA and near-complete full-length transcript coverage. Using RamDA-seq with differentiation time course samples of mouse embryonic stem cells, we reveal hundreds of dynamically regulated non-poly(A) transcripts, including histone transcripts and long noncoding RNA Neat1. Moreover, RamDA-seq profiles recursive splicing in >300-kb introns. RamDA-seq also detects enhancer RNAs and their cell type-specific activity in single cells. Taken together, we demonstrate that RamDA-seq could help investigate the dynamics of gene expression, RNA-processing events and transcriptional regulation in single cells. [Mh] Termos MeSH primário: Sequenciamento de Nucleotídeos em Larga Escala/métodos Células-Tronco Embrionárias Murinas/metabolismo Processamento de RNA RNA Longo não Codificante/genética RNA Mensageiro/genética Análise de Célula Única/métodos [Mh] Termos MeSH secundário: Animais Sequência de Bases Diferenciação Celular Elementos Facilitadores Genéticos Éxons Histonas/genética Histonas/metabolismo Íntrons Camundongos Células-Tronco Embrionárias Murinas/citologia RNA Longo não Codificante/metabolismo RNA Mensageiro/metabolismo Análise de Sequência de RNA Transcrição Genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Histones); 0 (NEAT1 long non-coding RNA, mouse); 0 (RNA, Long Noncoding); 0 (RNA, Messenger) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180307 [Lr] Data última revisão: 180307 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180214 [St] Status: MEDLINE [do] DOI: 10.1038/s41467-018-02866-0

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[PMID]: 29231014 [Au] Autor: Wu FY; Tang XH; Gai LL; Kong XP; Hao B; Huang EW; Shi H; Sheng LH; Quan L; Liu SP; Luo B [Ad] Endereço: Department of Forensic Medicine, Zhongshan Medical College, Sun Yat-sen University, Guangzhou 510080, China. [Ti] Título: [Correlation between Genetic Variants and Polymorphism of Caveolin and Sudden Unexplained Death]. [So] Source: Fa Yi Xue Za Zhi;33(2):114-119, 2017 Apr. [Is] ISSN: 1004-5619 [Cp] País de publicação: China [La] Idioma: chi [Ab] Resumo: OBJECTIVES: To explore the genetic variation sites of caveolin （CAV） and their correlation with sudden unexplained death （SUD）. METHODS: The blood samples were collected from SUD group （71 cases）, coronary artery disease （CAD） group （62 cases） and control group （60 cases）, respectively. The genome DNA were extracted and sequencing was performed directly by amplifying gene coding region and exon-intron splicing region of and using PCR. The type of heritable variation of was confirmed and statistical analysis was performed. RESULTS: A total of 4 variation sites that maybe significative were identified in SUD group, and two were newfound which were ： c.45C>T （T15T） and ：c.512G>A （R171H）, and two were SNP loci which were ：c.246C>T （rs35242077） and ：c.99C>T （rs1008642） and had significant difference （ <0.05） in allele and genotype frequencies between SUD and control groups. Forementioned variation sites were not found in CAD group. CONCLUSIONS: The variants of and may be correlated with a part of SUD group. [Mh] Termos MeSH primário: Caveolinas/genética Morte Súbita/etiologia Polimorfismo de Nucleotídeo Único [Mh] Termos MeSH secundário: Doença da Artéria Coronariana Éxons Genótipo Seres Humanos Masculino Reação em Cadeia da Polimerase [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Caveolins) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180308 [Lr] Data última revisão: 180308 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171213 [St] Status: MEDLINE [do] DOI: 10.3969/j.issn.1004-5619.2017.02.002

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[PMID]: 29397600 [Au] Autor: Weng Y; Xue SN; Zhang SL; Cheng H; Yan L [Ad] Endereço: Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. [Ti] Título: [A comparison of clinical characteristics between 2 pedigrees of multiple endocrine neoplasia type 2A with different RET mutations]. [So] Source: Zhonghua Nei Ke Za Zhi;57(2):134-137, 2018 Feb 01. [Is] ISSN: 0578-1426 [Cp] País de publicação: China [La] Idioma: chi [Ab] Resumo: Multiple endocrine neoplasia type 2A (MEN2A) is a hereditary syndrome. Here, two different RET proto-oncogen mutation were identified from family members of two MEN2A pedigrees by genetic screening. One RET mutations were found at codons 1893 and 1895 in exon 11 (1893-1895delCGA) from pedigree 1, which is a novel mutation, the other occurs at codon 634 (Cys634Arg) in exon 11 from pedigree 2. However, the clinical characteristics were similar in the patients of the two pedigrees. All the patients were in middle-age at onset. Most of them were firstly diagnosed with bilateral adrenal pheochromocytoma with different degrees of thyroid abnormalities (elevated serum calcitonin with or without thyroid mass, or had been diagnosed with medullary thyroid carcinoma). Some family members were with elevated serum parathyroid hormone but with no other evidences for hyperparathyroidism. [Mh] Termos MeSH primário: Neoplasias das Glândulas Suprarrenais/diagnóstico Neoplasia Endócrina Múltipla Tipo 2a/genética Mutação Feocromocitoma/diagnóstico Proteínas Proto-Oncogênicas c-ret/genética [Mh] Termos MeSH secundário: Neoplasias das Glândulas Suprarrenais/genética Carcinoma Neuroendócrino/diagnóstico Carcinoma Neuroendócrino/genética Éxons Seres Humanos Meia-Idade Neoplasia Endócrina Múltipla Tipo 2a/patologia Linhagem Feocromocitoma/genética Mutação Puntual Neoplasias da Glândula Tireoide/diagnóstico Neoplasias da Glândula Tireoide/genética [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: EC 2.7.10.1 (Proto-Oncogene Proteins c-ret) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180206 [St] Status: MEDLINE [do] DOI: 10.3760/cma.j.issn.0578-1426.2018.02.010

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[PMID]: 29390271 [Au] Autor: Li T; Zhang ZJ; Ma X; Lv X; Xiao H; Guo QN; Liu HY; Wang HD; Wu D; Lou GY; Wang X; Zhang CY; Liao SX [Ad] Endereço: Institute of Medical Genetics (Prenatal Diagnosis Center), People's Hospital of Zhengzhou University, Henan Provincial People's Hospital. [Ti] Título: Prenatal diagnosis for a Chinese family with a de novo DMD gene mutation: A case report. [So] Source: Medicine (Baltimore);96(50):e8814, 2017 Dec. [Is] ISSN: 1536-5964 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Patients with Duchenne muscular dystrophy (DMD) usually have severe and fatal symptoms. At present, there is no effective treatment for DMD, thus it is very important to avoid the birth of children with DMD by effective prenatal diagnosis. We identified a de novo DMD gene mutation in a Chinese family, and make a prenatal diagnosis. METHODS: First, multiplex ligation-dependent probe amplification (MLPA) was applied to analyze DMD gene exon deletion/duplication in all family members. The coding sequences of 79 exons in DMD gene were analyzed by Sanger sequencing in the patient; and then according to DMD gene exon mutation in the patient, DMD gene sequencing was performed in the family members. On the basis of results above, the pathogenic mutation in DMD gene was identified. RESULTS: MLPA showed no DMD gene exon deletion/duplication in all family members. Sanger sequencing revealed c.2767_2767delT [p.Ser923LeufsX26] mutation in DMD gene of the patient. Heterozygous deletion mutation (T/-) at this locus was observed in the pregnant woman and her mother and younger sister. The analyses of amniotic fluid samples indicated negative Y chromosome sex-determining gene, no DMD gene exon deletion/duplication, no mutations at c.2767 locus, and the inherited maternal X chromosome different from that of the patient. CONCLUSION: The pathogenic mutation in DMD gene, c.2767_2767delT [p.Ser923LeufsX26], identified in this family is a de novo mutation. On the basis of specific conditions, it is necessary to select suitable methods to make prenatal diagnosis more effective, accurate, and economic. [Mh] Termos MeSH primário: Distrofia Muscular de Duchenne/diagnóstico Distrofia Muscular de Duchenne/genética Diagnóstico Pré-Natal/métodos [Mh] Termos MeSH secundário: Adolescente Adulto Pré-Escolar China Éxons Feminino Predisposição Genética para Doença Seres Humanos Masculino Linhagem Gravidez Deleção de Sequência [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180301 [Lr] Data última revisão: 180301 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 180203 [St] Status: MEDLINE [do] DOI: 10.1097/MD.0000000000008814

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[PMID]: 29236709 [Au] Autor: Barrett SP; Parker KR; Horn C; Mata M; Salzman J [Ad] Endereço: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, United States of America. [Ti] Título: ciRS-7 exonic sequence is embedded in a long non-coding RNA locus. [So] Source: PLoS Genet;13(12):e1007114, 2017 12. [Is] ISSN: 1553-7404 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: ciRS-7 is an intensely studied, highly expressed and conserved circRNA. Essentially nothing is known about its biogenesis, including the location of its promoter. A prevailing assumption has been that ciRS-7 is an exceptional circRNA because it is transcribed from a locus lacking any mature linear RNA transcripts of the same sense. To study the biogenesis of ciRS-7, we developed an algorithm to define its promoter and predicted that the human ciRS-7 promoter coincides with that of the long non-coding RNA, LINC00632. We validated this prediction using multiple orthogonal experimental assays. We also used computational approaches and experimental validation to establish that ciRS-7 exonic sequence is embedded in linear transcripts that are flanked by cryptic exons in both human and mouse. Together, this experimental and computational evidence generates a new model for regulation of this locus: (a) ciRS-7 is like other circRNAs, as it is spliced into linear transcripts; (b) expression of ciRS-7 is primarily determined by the chromatin state of LINC00632 promoters; (c) transcription and splicing factors sufficient for ciRS-7 biogenesis are expressed in cells that lack detectable ciRS-7 expression. These findings have significant implications for the study of the regulation and function of ciRS-7, and the analytic framework we developed to jointly analyze RNA-seq and ChIP-seq data reveal the potential for genome-wide discovery of important biological regulation missed in current reference annotations. [Mh] Termos MeSH primário: RNA/biossíntese RNA/genética [Mh] Termos MeSH secundário: Algoritmos Processamento Alternativo Animais Química Encefálica Éxons Feminino Células HEK293 Seres Humanos Camundongos Gravidez Processamento de RNA RNA Longo não Codificante/genética Análise de Sequência de RNA/métodos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (RNA, Long Noncoding); 0 (RNA, circular); 63231-63-0 (RNA) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171214 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pgen.1007114

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[PMID]: 28943376 [Au] Autor: Kishida T; Suzuki M; Takayama A [Ad] Endereço: Wildlife Research Center, Kyoto University, 2-24 Tanaka Sekiden-cho, Sakyo, Kyoto 606-8203, Japan. Electronic address: taku.kishida@gmail.com. [Ti] Título: Evolution of the alternative AQP2 gene: Acquisition of a novel protein-coding sequence in dolphins. [So] Source: Mol Phylogenet Evol;118:54-57, 2018 Jan. [Is] ISSN: 1095-9513 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Taxon-specific de novo protein-coding sequences are thought to be important for taxon-specific environmental adaptation. A recent study revealed that bottlenose dolphins acquired a novel isoform of aquaporin 2 generated by alternative splicing (alternative AQP2), which helps dolphins to live in hyperosmotic seawater. The AQP2 gene consists of four exons, but the alternative AQP2 gene lacks the fourth exon and instead has a longer third exon that includes the original third exon and a part of the original third intron. Here, we show that the latter half of the third exon of the alternative AQP2 arose from a non-protein-coding sequence. Intact ORF of this de novo sequence is shared not by all cetaceans, but only by delphinoids. However, this sequence is conservative in all modern cetaceans, implying that this de novo sequence potentially plays important roles for marine adaptation in cetaceans. [Mh] Termos MeSH primário: Aquaporina 2/química Golfinhos/classificação Evolução Molecular [Mh] Termos MeSH secundário: Processamento Alternativo Animais Aquaporina 2/genética Aquaporina 2/metabolismo Sequência de Bases Golfinhos/metabolismo Éxons Íntrons Rim/metabolismo Filogenia Isoformas de Proteínas/química Isoformas de Proteínas/genética Isoformas de Proteínas/metabolismo RNA/química RNA/isolamento & purificação RNA/metabolismo Alinhamento de Sequência Análise de Sequência de DNA [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Aquaporin 2); 0 (Protein Isoforms); 63231-63-0 (RNA) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170926 [St] Status: MEDLINE

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[PMID]: 28454577 [Au] Autor: Marranci A; Jiang Z; Vitiello M; Guzzolino E; Comelli L; Sarti S; Lubrano S; Franchin C; Echevarría-Vargas I; Tuccoli A; Mercatanti A; Evangelista M; Sportoletti P; Cozza G; Luzi E; Capobianco E; Villanueva J; Arrigoni G; Signore G; Rocchiccioli S; Pitto L; Tsinoremas N; Poliseno L [Ad] Endereço: Oncogenomics Unit, Core Research Laboratory, Istituto Toscano Tumori (ITT), AOUP, CNR-IFC, Via Moruzzi 1, 56124, Pisa, Italy. [Ti] Título: The landscape of BRAF transcript and protein variants in human cancer. [So] Source: Mol Cancer;16(1):85, 2017 04 28. [Is] ISSN: 1476-4598 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood. RESULTS: Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3-10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3-10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation. CONCLUSIONS: By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies. [Mh] Termos MeSH primário: Melanoma/genética Neoplasias/genética Isoformas de Proteínas/genética Proteínas Proto-Oncogênicas B-raf/genética [Mh] Termos MeSH secundário: Processamento Alternativo/genética Linhagem Celular Tumoral Resistência a Medicamentos Antineoplásicos/genética Éxons/genética Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Indóis/administração & dosagem Melanoma/tratamento farmacológico Melanoma/patologia Neoplasias/tratamento farmacológico Neoplasias/patologia RNA Mensageiro/genética Sulfonamidas/administração & dosagem [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Indoles); 0 (Protein Isoforms); 0 (RNA, Messenger); 0 (Sulfonamides); 207SMY3FQT (vemurafenib); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE [do] DOI: 10.1186/s12943-017-0645-4

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[PMID]: 28460014 [Au] Autor: Wu X; Wang SH; Sun J; Krainer AR; Hua Y; Prior TW [Ad] Endereço: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China. [Ti] Título: A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. [So] Source: Hum Mol Genet;26(14):2768-2780, 2017 07 15. [Is] ISSN: 1460-2083 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859G > C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6T transition, no other changes were detected. Analyzed with minigenes, SMN1C6T displayed a ∼20% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6. Using RNA-affinity chromatography and mass spectrometry, we further uncovered binding of the RNA-binding protein HuR to the -44 region, where it acts as a splicing repressor. The A-44G change markedly decreases the binding affinity of HuR, resulting in a moderate increase in exon 7 inclusion. [Mh] Termos MeSH primário: Atrofia Muscular Espinal/genética [Mh] Termos MeSH secundário: Animais Células COS Cercopithecus aethiops Proteína Semelhante a ELAV 1/metabolismo Éxons Células HEK293 Células HeLa Seres Humanos Íntrons Atrofia Muscular Espinal/metabolismo Ligação Proteica RNA/genética Motivo de Reconhecimento de RNA Processamento de RNA Proteína 1 de Sobrevivência do Neurônio Motor/genética Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo Proteína 2 de Sobrevivência do Neurônio Motor/genética Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (SMN1 protein, human); 0 (SMN2 protein, human); 0 (Survival of Motor Neuron 1 Protein); 0 (Survival of Motor Neuron 2 Protein); 63231-63-0 (RNA) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180225 [Lr] Data última revisão: 180225 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170502 [St] Status: MEDLINE [do] DOI: 10.1093/hmg/ddx166

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2	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2
3	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2

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