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1.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203967

RESUMO

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.


Assuntos
Análise Custo-Benefício , Éxons/genética , Proteínas da Matriz Extracelular/genética , Sondas Moleculares/metabolismo , Sítios de Splice de RNA/genética , Retinite Pigmentosa/genética , Análise de Sequência de DNA , Síndromes de Usher/genética , Sequência de Bases , Variações do Número de Cópias de DNA/genética , Deleção de Genes , Humanos , Polimorfismo de Nucleotídeo Único/genética , Retinite Pigmentosa/economia , Síndromes de Usher/economia
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(6): 658-665, 2021 Jun 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34275936

RESUMO

X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the PHEX gene and is the most common form of hereditary rickets. The treatment is more complicated compared with the general rickets. A family were admitted to the Department of Endocrinology, Hainan General Hospital in 2018. The proband was a 3-year-6-month-old female, Han nationality. She was admitted to hospitalization for bilateral knee valgus and walking instability. The patient's parents were not in consanguineous marrige, and there was no similar medical history in the family. The patient presented with "O" leg, bracelet sign, chicken breast, and low blood phosphorus. Typical change of rickets also appeared in her X-ray examination. The DNAs of the peripheral blood were extracted from the patient and her parents. All coding exons and flanking regions of PHEX gene in the patient were amplified by PCR, and the mutant sites of the family members were testified by a generation sequencing. A heterozygous variation (c.1482+5G>C) affecting splicing outcome was detected at the splicing region of intron 13 of PHEX gene in the patient. The variation has been included in the human gene mutation database (HGMD). No variation was found in the proband's parents, the PHEX gene in the patient was a de novo variation. Our research provided reference for the future genetic counseling for this patient and enriched the research data on the relationship between genotype and clinical manifestations.


Assuntos
Raquitismo Hipofosfatêmico Familiar , Éxons/genética , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Humanos , Lactente , Íntrons , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética
3.
Nat Commun ; 12(1): 4212, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244496

RESUMO

CSR-1 is an essential Argonaute protein that binds to a subclass of 22G-RNAs targeting most germline-expressed genes. Here we show that the two isoforms of CSR-1 have distinct expression patterns; CSR-1B is ubiquitously expressed throughout the germline and during all stages of development while CSR-1A expression is restricted to germ cells undergoing spermatogenesis. Furthermore, CSR-1A associates preferentially with 22G-RNAs mapping to spermatogenesis-specific genes whereas CSR-1B-bound small RNAs map predominantly to oogenesis-specific genes. Interestingly, the exon unique to CSR-1A contains multiple dimethylarginine modifications, which are necessary for the preferential binding of CSR-1A to spermatogenesis-specific 22G-RNAs. Thus, we have discovered a regulatory mechanism for C. elegans Argonaute proteins that allows for specificity of small RNA binding between similar Argonaute proteins with overlapping temporal and spatial localization.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Interferência de RNA , Espermatogênese/genética , Animais , Animais Geneticamente Modificados , Arginina/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Éxons/genética , Feminino , Masculino , Metilação , Oogênese/genética , Ligação Proteica/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno/metabolismo , Processos de Determinação Sexual/genética
4.
BMJ Case Rep ; 14(6)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193451

RESUMO

Ataxia with oculomotor apraxia type 2 (AOA2), recently renamed as ATX-SETX, is an autosomal recessive, progressive neurodegenerative disorder belonging to inherited cerebellar ataxias. The pathogenic variants of the SETX gene have been implicated in ATX-SETX. We report the case of a 21-year-old woman presenting with ataxia, oculomotor apraxia and dystonia. She had elevated serum α-fetoprotein (AFP), follicle stimulating hormone (FSH) and luteinising hormone (LH) levels and moderate cerebellar atrophy. On further evaluation, she was found to have premature ovarian failure as well. Multiplex ligation-dependent probe amplification detected a heterozygous deletion in exon 6 of the SETX gene. A combination of cerebellar ataxia, oculomotor apraxia with elevated AFP and cerebellar atrophy are highly suggestive of ATX-SETX. In rare instances, it may be associated with premature ovarian failure with elevated FSH and LH levels, necessitating hormonal survey and fertility evaluation in all patients with ATX-SETX.


Assuntos
Apraxias , Ataxia Cerebelar , Adulto , Apraxias/genética , Ataxia , Ataxia Cerebelar/genética , DNA Helicases , Éxons/genética , Feminino , Humanos , Enzimas Multifuncionais , RNA Helicases/genética , Ataxias Espinocerebelares/congênito , Adulto Jovem
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(6): 549-552, 2021 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-34096023

RESUMO

OBJECTIVE: To explore the genetic basis for a pedigree affected with hereditary multiple osteochondroma (HMO). METHODS: Peripheral blood samples were collected from the proband and members of his pedigree with informed consent. Following extraction of genomic DNA, all coding exons and flanking intronic sequences (-10 bp) of the EXT1 and EXT2 genes were subjected to targeted capture and next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing. RESULTS: A heterozygous nonsense variant (c.1911C>A) was found in exon 10 of the EXT1 gene in the proband and his affected father but not in a healthy sister and normal controls. The variant was classified as a pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (PVS1+PM2+PP1). Bioinformatic analysis predicted that the c.1911C>A variant may be disease-causing via nonsense-mediated mRNA decay and anomalous splicing. CONCLUSION: The c.1911C>A variant probably underlay the disease in this pedigree. Discovery of this variant enriched the variant spectrum of HMO.


Assuntos
Exostose Múltipla Hereditária , Códon sem Sentido , Éxons/genética , Exostose Múltipla Hereditária/genética , Heterozigoto , Humanos , Linhagem
6.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066408

RESUMO

WUSCHEL-related homeobox (WOX) transcription factors (TFs) are well known for their role in plant development but are rarely studied in citrus. In this study, we identified 11 putative genes from the sweet orange genome and divided the citrus WOX genes into three clades (modern/WUSCHEL(WUS), intermediate, and ancient). Subsequently, we performed syntenic relationship, intron-exon organization, motif composition, and cis-element analysis. Co-expression analysis based on RNA-seq and tissue-specific expression patterns revealed that CsWOX gene expression has multiple intrinsic functions. CsWUS homolog of AtWUS functions as a transcriptional activator and binds to specific DNA. Overexpression of CsWUS in tobacco revealed dramatic phenotypic changes, including malformed leaves and reduced gynoecia with no seed development. Silencing of CsWUS in lemon using the virus-induced gene silencing (VIGS) system implied the involvement of CsWUS in cells of the plant stem. In addition, CsWUS was found to interact with CsCYCD3, an ortholog in Arabidopsis (AtCYCD3,1). Yeast one-hybrid screening and dual luciferase activity revealed that two TFs (CsRAP2.12 and CsHB22) bind to the promoter of CsWUS and regulate its expression. Altogether, these results extend our knowledge of the WOX gene family along with CsWUS function and provide valuable findings for future study on development regulation and comprehensive data of WOX members in citrus.


Assuntos
Citrus sinensis/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Família Multigênica , Proteínas de Plantas/genética , Simulação por Computador , Sequência Conservada/genética , Éxons/genética , Flores/genética , Inativação Gênica , Íntrons/genética , Motivos de Nucleotídeos/genética , Fenótipo , Filogenia , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Mapas de Interação de Proteínas/genética , Frações Subcelulares/metabolismo , Sintenia/genética , Tabaco/genética , Água
7.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064652

RESUMO

The neuronal Hu/ELAV-like proteins HuB, HuC and HuD are a class of RNA-binding proteins that are crucial for proper development and maintenance of the nervous system. These proteins bind to AU-rich elements (AREs) in the untranslated regions (3'-UTRs) of target mRNAs regulating mRNA stability, transport and translation. In addition to these cytoplasmic functions, Hu proteins have been implicated in alternative splicing and alternative polyadenylation in the nucleus. The purpose of this study was to identify transcriptome-wide effects of HuD deletion on both of these nuclear events using RNA sequencing data obtained from the neocortex of Elavl4-/- (HuD KO) mice. HuD KO affected alternative splicing of 310 genes, including 17 validated HuD targets such as Cbx3, Cspp1, Snap25 and Gria2. In addition, deletion of HuD affected polyadenylation of 53 genes, with the majority of significantly altered mRNAs shifting towards usage of proximal polyadenylation signals (PAS), resulting in shorter 3'-UTRs. None of these genes overlapped with those showing alternative splicing events. Overall, HuD KO had a greater effect on alternative splicing than polyadenylation, with many of the affected genes implicated in several neuronal functions and neuropsychiatric disorders.


Assuntos
Processamento Alternativo/genética , Proteína Semelhante a ELAV 4/genética , Neocórtex/metabolismo , Poliadenilação/genética , Animais , Proteína Semelhante a ELAV 4/metabolismo , Éxons/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
8.
Stem Cell Res ; 53: 102366, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087995

RESUMO

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder caused by defects in the Notch signaling pathway, including the mutation in JAGGED1 (JAG1) (ALGS type 1) or NOTCH2 (ALGS type 2). An induced pluripotent stem cell (iPSC) line was generated from the dermal fibroblasts of a 3-month-old patient with heterozygous mutation at JAG1 splicing site (Chr20: 10,629,709C>A) before exon 11. This iPSC model offers a useful resource for disease modeling to study the disease pathophysiology and to develop therapeutics for treatment of ALGS.


Assuntos
Síndrome de Alagille , Células-Tronco Pluripotentes Induzidas , Síndrome de Alagille/genética , Éxons/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lactente , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Mutação
9.
BioDrugs ; 35(4): 389-399, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34097287

RESUMO

The debilitating neuromuscular disorders Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which harm 1 in 5000 newborn males and 1 in 11,000 newborns, respectively, are marked by progressive muscle wasting among other complications. While DMD causes generalized muscle weakness due to the absence of the dystrophin protein, SMA patients generally face motor neuron degeneration because of the lack of the survival motor neuron (SMN) protein. Many of the most promising therapies for both conditions restore the absent proteins dystrophin and SMN. Antisense oligonucleotide-mediated exon skipping and inclusion therapies are advancing clinically with the approved DMD therapies casimersen, eteplirsen, golodirsen, and viltolarsen, and the SMA therapy nusinersen. Existing antisense therapies focus on skeletal muscle for DMD and motor neurons for SMA, respectively. Through innovative techniques, such as peptide conjugation and multi-exon skipping, these therapies could be optimized for efficacy and applicability. By contrast, gene replacement therapy is administered only once to patients during treatment. Currently, only onasemnogene abeparvovec for SMA has been approved. Safety shortcomings remain a major challenge for gene therapy. Nevertheless, gene therapy for DMD has strong potential to restore dystrophin expression in patients. In light of promising functional improvements, antisense and gene therapies stand poised to elevate the lives of patients with DMD and SMA.


Assuntos
Atrofia Muscular Espinal , Distrofia Muscular de Duchenne , Éxons/genética , Terapia Genética , Humanos , Recém-Nascido , Masculino , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Oligonucleotídeos
10.
Nat Commun ; 12(1): 3750, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145229

RESUMO

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.


Assuntos
Adenosina Trifosfatases/genética , Transtorno Bipolar/genética , Exoma/genética , Predisposição Genética para Doença/genética , Adulto , Éxons/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma
11.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065232

RESUMO

Tau protein is largely responsible for tauopathies, including Alzheimer's disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3ß, whose activity is inhibited by the cellular prion protein (PrPC), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrPC and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrPC and the implication of GSK3ß in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrPC ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrPC expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrPC levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3ß activity downstream from PrPC in this phenomenon. Our results indicate that PrPC plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3ß.


Assuntos
Regulação para Baixo/genética , Éxons/genética , Glicogênio Sintase Quinase 3 beta/genética , Príons/genética , Proteínas tau/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo/genética , Doença de Alzheimer/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Corpos de Inclusão/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neurônios/patologia , Isoformas de Proteínas/genética , RNA Mensageiro/genética , Tauopatias/genética
12.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065499

RESUMO

Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T>C leads to exon skipping while the novel deep intronic variant c.1033-327T>A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals.


Assuntos
Proteínas de Ciclo Celular/genética , Distrofia de Cones/genética , Íntrons/genética , Mutação/genética , Sítios de Splice de RNA/genética , Splicing de RNA/genética , Degeneração Retiniana/genética , Adolescente , Adulto , Éxons/genética , Feminino , Células HEK293 , Heterozigoto , Homozigoto , Humanos , Masculino , Retinite Pigmentosa/genética , Virulência/genética , Adulto Jovem
13.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067314

RESUMO

Cholinergic α7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5-7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a, resulting in a hybrid gene known as CHRFAM7A, unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer's diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca2+ conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/dupα7 interfaces. Based on these models, we used protein-protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aß42. Our findings show that the optimal stoichiometry of dupα7/α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aß42 effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in 'Alzheimer's disease research.


Assuntos
Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Éxons/genética , Duplicação Gênica/genética , Humanos , Ligantes , Camundongos
14.
J Pak Med Assoc ; 71(6): 1633-1638, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34111087

RESUMO

OBJECTIVE: Intrahepatic Cholestasis of Pregnancy (ICP) is a rare pregnancy specific disorder. Genetic variants of ABCB4 gene increase ICP risk. This study was conducted to determine frequency of ICP cases presented at a tertiary care hospital in Rawalpindi, Pakistan and to screen for genetic variants of exon 6 and 14 of ABCB4 gene in ICP cases. METHODS: This analytical study included ICP patients presenting at Department of Gynaecology and Obstetrics, Holy Family Hospital Rawalpindi, from February 2017 to May 2017. Sanger's sequencing was performed using genomic DNA extracted from blood samples of patients and controls. RESULTS: Twenty pregnant women out of 1150 (1.74%) had ICP and were enrolled during study period. Overall (19/20) 95% patients had pruritus and among them (8/20) 40%, (4/20) 20% and (2/20) 10% had a history of miscarriages, stillbirths and familial ICP respectively. Genetic analysis revealed an already reported variant i.e., c.504C>T in exon 6 in thirteen patients and a novel variant i.e., c.1686A>G in exon 14 in five patients. Both variants were not present in controls. In silico analysis suggested that both variants might affect pre-mRNA splicing of ABCB4 transcript. CONCLUSIONS: ICP had a frequency of 1.74% among pregnant women. Identification of a novel heterozygous variant in five patients and an already reported variant in thirteen patients reaffirms genetic heterogeneity and role of ABCB4 in ICP etiology.


Assuntos
Colestase Intra-Hepática , Complicações na Gravidez , Colestase Intra-Hepática/epidemiologia , Colestase Intra-Hepática/genética , Éxons/genética , Feminino , Humanos , Paquistão , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Centros de Atenção Terciária
15.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947059

RESUMO

Crop domestication, which gives rise to a number of desirable agronomic traits, represents a typical model system of plant evolution. Numerous genomic evidence has proven that noncoding RNAs such as microRNAs and phasiRNAs, as well as protein-coding genes, are selected during crop domestication. However, limited data shows plant long noncoding RNAs (lncRNAs) are also involved in this biological process. In this study, we performed strand-specific RNA sequencing of cultivated rice Oryza sativa ssp. japonica and O. sativa ssp. indica, and their wild progenitor O. rufipogon. We identified a total of 8528 lncRNAs, including 4072 lncRNAs in O. rufipogon, 2091 lncRNAs in japonica rice, and 2365 lncRNAs in indica rice. The lncRNAs expressed in wild rice were revealed to be shorter in length and had fewer exon numbers when compared with lncRNAs from cultivated rice. We also identified a number of conserved lncRNAs in the wild and cultivated rice. The functional study demonstrated that several of these conserved lncRNAs are associated with domestication-related traits in rice. Our findings revealed the feature and conservation of lncRNAs during rice domestication and will further promote functional studies of lncRNAs in rice.


Assuntos
Domesticação , Estudo de Associação Genômica Ampla , Oryza/genética , RNA Longo não Codificante/genética , RNA de Plantas/genética , Sequência de Bases , Sequência Conservada , Produtos Agrícolas/genética , Éxons/genética , Biblioteca Gênica , Anotação de Sequência Molecular , RNA Longo não Codificante/isolamento & purificação , RNA de Plantas/isolamento & purificação , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Transcriptoma
16.
Nat Commun ; 12(1): 2756, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980843

RESUMO

High-throughput splicing assays have demonstrated that many exonic variants can disrupt splicing; however, splice-disrupting variants distribute non-uniformly across genes. We propose the existence of exons that are particularly susceptible to splice-disrupting variants, which we refer to as hotspot exons. Hotspot exons are also more susceptible to splicing perturbation through drug treatment and knock-down of RNA-binding proteins. We develop a classifier for exonic splice-disrupting variants and use it to infer hotspot exons. We estimate that 1400 exons in the human genome are hotspots. Using panels of splicing reporters, we demonstrate how the ability of an exon to tolerate a mutation is inversely proportional to the strength of its neighboring splice sites.


Assuntos
Éxons/genética , Variação Genética , Splicing de RNA/genética , Processamento Alternativo/genética , Sítios de Ligação , Regulação da Expressão Gênica , Genoma Humano , Humanos , Mutação , Sítios de Splice de RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
17.
Gan To Kagaku Ryoho ; 48(5): 673-676, 2021 May.
Artigo em Japonês | MEDLINE | ID: mdl-34006711

RESUMO

Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase the signaling of which is important for growth and progression of cancer. An exon 19 deletion mutation and an exon 21 L858R point mutation are frequently detected as EGFR mutations in patients with non‒small cell lung cancer. This review summarizes the differences in epidemiological, nonclinical, and clinical characteristics between the exon 19 deletion mutation and the exon 21 L858R point mutation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Éxons/genética , Humanos , Neoplasias Pulmonares/genética , Mutação , Mutação Puntual , Inibidores de Proteínas Quinases
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(5): 425-429, 2021 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-33974248

RESUMO

OBJECTIVE: To summarize the result of genetic testing and therapeutic prospect of 2042 unrelated Chinese pedigrees affected with Duchenne/Becker muscular dystrophy (DMD/BMD) from a single center from 2005 to 2019. METHODS: Peripheral blood samples of the pedigrees were collected for the detection of DMD gene variants with combined multiple ligation-dependent probe amplification (MLPA), next generation sequencing (NGS) and Sanger sequencing. RESULTS: DMD and BMD have respectively accounted for 78.60% and 21.40% of the pedigrees, which included 33 female probands. Variants of the DMD gene were detected in 1986 pedigrees (97.26%). Large deletions, duplications and small-scale mutations have respectively accounted for 71.85%, 8.76% and 19.39%. Common deletions and duplications have included deletion of exons 45-50 and duplications of exon 2, while no hot spot was found with small-scale mutations. For 1595 pedigrees affected with DMD, 935 (58.62%) were hereditary and 660 (41.38%) were de novo in origin. 34.28% (700/2042) of the patients had symptoms which could be relieved by gene therapy. CONCLUSION: This has been the largest single-center study of DMD pedigrees, which has attained definite diagnosis in 97.26% of the patients. The results have enabled genetic counseling and prenatal diagnosis for the affected families upon their subsequent pregnancies, enriched the spectrum of DMD gene variants, as well as facilitated study of the mechanism of DMD gene mutations and exploration of clinical treatment.


Assuntos
Distrofia Muscular de Duchenne , China , Distrofina/genética , Éxons/genética , Feminino , Deleção de Genes , Testes Genéticos , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Mutação , Linhagem , Gravidez
19.
Biomed Res Int ; 2021: 7509825, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33969125

RESUMO

Juvenile myoclonic epilepsy (JME) is the most prevalent and genetically heterogeneous form of epilepsy and accounts for 10-30% of all the cases worldwide. Ef-hand domain- (c-terminal-) containing protein 1 (EFHC1) encodes for a nonion channel protein and mutations in this gene have been extensively reported in different populations to play a causative role in JME. Linkage between JME and 6p11-12 locus has already been confirmed in Mexican and Dutch families. A case-control study was conducted on Pakistani JME patients for the first time, aimed at finding out EFHC1 mutations that have been reported in different populations. For this purpose, 66 clinically diagnosed JME patients and 108 control subjects were included in the study. Blood samples were collected from all the participants, and DNA was isolated from the lymphocytes by the modified organic method. Total 3 exons of EFHC1, harboring extensively reported mutations, were selected for genotypic analysis. We identified three heterozygous variants, R159W, V460A, P436P, and one insertion in the current study. V460A, an uncommon variant identified herein, has recently been reported in public databases in an unphenotyped American individual. This missense variant was found in 3 Pakistani JME patients from 2 unrelated families. However, in silico analysis showed that V460A may possibly be a neutral variant. While the absence of a majority of previously reported mutations in our population suggests that most of the mutations of EFHC1 are confined to particular ethnicities and are not evenly distributed across the world. However, to imply the causation, the whole gene and larger number of JME patients should be screened in this understudied population.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Epilepsia Mioclônica Juvenil/genética , Adolescente , Sequência de Bases , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Masculino , Mutação/genética , Paquistão
20.
J Med Case Rep ; 15(1): 263, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33941229

RESUMO

BACKGROUND: Germline pathogenic variants in the cadherin-1 (CDH1) gene cause a predisposition to hereditary diffuse gastric cancer (HDGC). We report an HDGC case in Vietnam and identify a novel mutation in the CDH1 gene. CASE PRESENTATION: A 28-year-old Vietnamese man was diagnosed with HDGC and a novel mutation at c.639G>A. All exons of CDH1 were sequenced in his pedigree, which revealed the c.639G>A mutation in the proband, his father, and uncle. The patient refused treatment and died 4 months after diagnosis. Endoscopic surveillance of the father and the uncle showed structural abnormalities in the father. CONCLUSION: In cases of HDGC, identification of the CDH1 gene mutation is very important for better counseling and more effective strategies to prevent the development of diseases, such as prophylactic gastrectomy for family members with genetic mutations.


Assuntos
Neoplasias Gástricas , Adulto , Grupo com Ancestrais do Continente Asiático , Caderinas/genética , Códon de Terminação , Éxons/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Mutação , Linhagem , Neoplasias Gástricas/genética
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