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The OAS-RNase L pathway is one of the oldest innate RNA sensing pathways that leads to interferon (IFN) signaling and cell death. OAS recognizes viral RNA and then activates RNase L, which subsequently cleaves both cellular and viral RNA, creating "processed RNA" as an endogenous ligand that further triggers RIG-I-like receptor signaling. However, the IFN response and antiviral activity of the OAS-RNase L pathway are weak compared to other RNA-sensing pathways. Here, we discover that the SKIV2L RNA exosome limits the antiviral capacity of the OAS-RNase L pathway. SKIV2L-deficient cells exhibit remarkably increased interferon responses to RNase L-processed RNA, resulting in heightened antiviral activity. The helicase activity of SKIV2L is indispensable for this function, acting downstream of RNase L. SKIV2L depletion increases the antiviral capacity of OAS-RNase L against RNA virus infection. Furthermore, SKIV2L loss exacerbates autoinflammation caused by human OAS1 gain-of-function mutations. Taken together, our results identify SKIV2L as a critical barrier to OAS-RNase L-mediated antiviral immunity that could be therapeutically targeted to enhance the activity of a basic antiviral pathway.
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Background: Trichohepatoenteric syndrome (THES) is a rare Mendelian autosomal recessive genetic disease characterized by intractable diarrhea, woolly hair, facial abnormality, immune dysfunction, and intrauterine growth restriction. THES mutations are found in the TTC37 and SKIV2L genes, which encode two components of the human superkiller (SKI) complex. Methods and results: We report one case of a 32-year-old woman of Chinese descent with THES, who was born with a low weight (2000 g). She had intractable diarrhea during the neonatal period and was allergic to cow's milk and condensed milk, but did not require total parenteral nutrition. She experienced menarche at age 12 and amenorrhea at age 28. In May 2019, the patient presented with a left fibular head fracture and was diagnosed with osteoporosis. Genetic testing showed a novel mutation in exon1 [p.E5Afs∗37 (c.12_13del)] of SKIV2L, which is composed of 28 exons. After the diagnosis, hormone replacement therapy was prescribed, in addition to the routine calcium and vitamin D supplements. Conclusion: This case expands the clinical characteristic and phenotype spectrum of THES, providing further understanding of SKIV2L and its autoimmune influence.
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Congenital enteropathies (CE) are a group of rare inherited diseases with a typical onset early in life. They involve defects in enterocyte structure or differentiation. They can cause a severe condition of intestinal failure (IF). The diagnostic approach is based first on clinical presentation (consanguinity, prenatal expression, polyhydramnios, early neonatal onset, aspect of stools, persistence at bowel rest, associated extra-digestive manifestations .) and histo-pathological analyses. These rare intestinal diseases cause protracted diarrhea that might resolve, for a few, with a dietetic approach. However, protracted or permanent IF may require long term parenteral nutrition and, in limited cases, intestinal transplantation. With the progresses in both clinical nutrition and genetics, many of these CE are nowadays associated with recognized gene mutations. It improved our knowledge and the understanding in the patho-physiology of these diseases, thus, leading potentially to therapeutic perspectives. These review cover most of the early onset CE and excludes the immune related diarrhea.
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Enterocitos , Enfermedades Intestinales , Diarrea/etiología , Diarrea/terapia , Enterocitos/patología , Humanos , Recién Nacido , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/genética , Enfermedades Intestinales/terapia , Intestinos/patología , Nutrición ParenteralRESUMEN
Trichohepatoenteric syndrome (THES) is a rare autosomal recessive genetic disease characterized by severe early onset diarrhea, woolly and brittle hair, immunodeficiency, and liver disease. A mutation in either SKIV2L or TTC37 genes can cause the disease. We report a case of a 41-month-old girl who suffered from intractable watery diarrhea, hair abnormality, dysmorphic features, and poor weight gain. The diagnosis was made through whole-exome sequencing analysis. The analysis detected a new variant mutation (c.1201G > A) p. (Glu401Lys) in the SKIV2L gene. She was admitted once for poor weight gain and nasogastric tube (NGT) feeding, with which the patient showed improvement. She was discharged to go home on hypoallergenic baby formulas and a regular diet with improved weight gain.
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Background: Trichohepatoenteric syndrome (THES) is a rare disease that mainly causes intractable diarrhea. It is classified into THES1 and THES2, which are associated with the tetratricopeptide repeat domain 37 (TTC37) gene and Ski2-like RNA helicase (SKIV2L) gene, respectively. THES is not very prevalent in China or worldwide, but new cases have increasingly been reported. Methods and Results: Here, we report the clinical and genetic information of a 1.5-month-old girl who was admitted to our hospital due to diarrhea and failure to thrive. Whole-exome sequencing (WES) revealed novel compound-heterozygous variants of the SKIV2L gene, c.3602_3609delAGCGCCTG (p.Q1201Rfs*2), and c.1990A > G (p.T664A) as the causative factors, which were confirmed via Sanger sequencing. Upon continuous feeding with an amino-acid formula through a gastric tube and parenteral nutrition, the patient resumed thriving and her stool frequency decreased. Conclusion: We report a girl carrying novel variants of the SKIV2L gene that cause THES2, thereby providing valuable information on the diagnosis of THES2 and expanding the spectrum of disease-causing SKIV2L mutations.
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RNA decay is crucial for mRNA turnover and surveillance and misregulated in many diseases. This complex system is challenging to study, particularly in mammals, where it remains unclear whether decay pathways perform specialized versus redundant roles. Cytoplasmic pathways and links to translation are particularly enigmatic. By directly profiling decay factor targets and normal versus aberrant translation in mouse embryonic stem cells (mESCs), we uncovered extensive decay pathway specialization and crosstalk with translation. XRN1 (5'-3') mediates cytoplasmic bulk mRNA turnover whereas SKIV2L (3'-5') is universally recruited by ribosomes, tackling aberrant translation and sometimes modulating mRNA abundance. Further exploring translation surveillance revealed AVEN and FOCAD as SKIV2L interactors. AVEN prevents ribosome stalls at structured regions, which otherwise require SKIV2L for clearance. This pathway is crucial for histone translation, upstream open reading frame (uORF) regulation, and counteracting ribosome arrest on small ORFs. In summary, we uncovered key targets, components, and functions of mammalian RNA decay pathways and extensive coupling to translation.
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Proteínas Reguladoras de la Apoptosis/fisiología , Proteínas de Unión al ADN/fisiología , Exorribonucleasas/fisiología , Células Madre Embrionarias de Ratones/metabolismo , Biosíntesis de Proteínas , ARN Helicasas/fisiología , Estabilidad del ARN , ARN Mensajero/metabolismo , Animales , Sistemas CRISPR-Cas , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Madre Embrionarias de Ratones/citología , Sistemas de Lectura Abierta , Proteínas Proto-Oncogénicas/fisiología , ARN Mensajero/química , ARN Mensajero/genética , Ribosomas/genética , Ribosomas/metabolismoRESUMEN
At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 5' triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3'â5' through the Ski-exosome complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5' caps and destruction of faulty adducts in 5'â3' fashion; and (d) STK19 on nuclear protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease.
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ADN Helicasas , Exorribonucleasas , Complejo Mayor de Histocompatibilidad/genética , Proteínas Nucleares , Proteínas Serina-Treonina Quinasas , ARN/metabolismo , Factores de Transcripción , Animales , ADN Helicasas/genética , ADN Helicasas/fisiología , Exorribonucleasas/genética , Exorribonucleasas/fisiología , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/fisiología , Factores de Transcripción/genética , Factores de Transcripción/fisiologíaRESUMEN
Tricho-hepatic-enteric syndrome (THES) is a genetically heterogeneous rare syndrome (OMIM: 222470 (THES1) and 614602 (THES2)) that typically presents in the neonatal period with intractable diarrhoea, intra-uterine growth retardation (IUGR), facial dysmorphism, and hair and skin changes. THES is associated with pathogenic variants in either TTC37 or SKIV2L; both are components of the human SKI complex, an RNA exosome cofactor. We report an 8â¯year old girl who was diagnosed with THES by the Undiagnosed Disease Program-WA with compound heterozygous pathogenic variants in SKIV2L. While THES was considered in the differential diagnosis, the absence of protracted diarrhoea delayed definitive diagnosis. We therefore suggest that SKIV2L testing should be considered in cases otherwise suggestive of THES, but without the characteristic diarrhoea. We expand the phenotypic spectrum while reviewing the current knowledge on SKIV2L.
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Diarrea Infantil/diagnóstico , Diarrea Infantil/genética , Diarrea/diagnóstico , Diarrea/genética , Retardo del Crecimiento Fetal/diagnóstico , Retardo del Crecimiento Fetal/genética , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/genética , ADN Helicasas/genética , Facies , Heterocigoto , HumanosRESUMEN
Hepatitis B virus (HBV) -x protein is a transcriptional regulator required for the HBV life cycle. HBx also induces complications in the host such as hepatocellular carcinoma. We previously showed that HBx mRNA is degraded by the Ski2/RNA exosome complex. In the present study, we report the regulation of this system through the control of Ski2 expression. We identified interleukin (IL) -1ß as an inducer of expression from the Ski2 promoter. IL-1ß induced the expression of ATF3 transcription factor, which in turn binds to cyclic AMP-responsive element sequence in the Ski2 promoter and is responsible for Ski2 promoter induction by IL-1ß. We previously reported that Ski2 expression increases HBx mRNA degradation; consistent with those data, we showed here that HBx mRNA is degraded in response to IL-1ß treatment. Interestingly, HBx also significantly induced Ski2 expression. To our knowledge, this is the first report to show activation of the Ski2/RNA exosome complex by both the host and HBV. Understanding the regulation of the Ski2/RNA exosome system is expected to facilitate prevention of HBx-mediated complications through targeting the posttranscriptional degradation of HBx mRNA; and will also help shedding a light on the role of RNA decay systems in inflammation.
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Factor de Transcripción Activador 3/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Interleucina-1beta/metabolismo , ARN Mensajero/metabolismo , Transactivadores/metabolismo , Animales , Células Cultivadas , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Células Hep G2 , Humanos , Ratones , Ratones SCID , Ratones Transgénicos , ARN Mensajero/genética , Transactivadores/genética , Proteínas Reguladoras y Accesorias ViralesRESUMEN
The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37, two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37-mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.
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Linfocitos B/inmunología , Diarrea Infantil/complicaciones , Enfermedades del Cabello/complicaciones , Síndromes de Inmunodeficiencia/etiología , Células Asesinas Naturales/inmunología , Proteínas Portadoras/genética , Estudios de Cohortes , ADN Helicasas/genética , Diarrea Infantil/inmunología , Facies , Retardo del Crecimiento Fetal/inmunología , Enfermedades del Cabello/inmunología , Humanos , Síndromes de Inmunodeficiencia/genética , Memoria Inmunológica , Lactante , Recién Nacido , Interferón gamma/inmunología , Células Asesinas Naturales/patología , Recuento de Linfocitos , Mutación , Linfocitos T/inmunologíaRESUMEN
Tricho-Hepato-Enteric syndrome (THES) is a very rare autosomal recessive syndromic enteropathy caused by mutations of either TTC37 or SKIV2L genes. Very little is known of these two gene products in mammals nor of the pathophysiology of the disease. Since the identification of the genes, we have set up the molecular diagnostic of THES in routine, gathering a large cohort with clinical and molecular data. Here, we report the phenotype and genotype analysis of this cohort together with an extensive literature review of THES cases worldwide, that is, 96 individuals harboring mutations in one gene or the other. We set up locus-specific databases for both genes and reviewed the type of mutation as well as their localization in the proteins. No hot spot is evidenced for any type of mutation. The phenotypic analysis was first made on the whole cohort but is limited due to heterogeneity in clinical descriptions. We then examined the lab diagnostic cohort in detail for clinical manifestations. For the first time, we are able to suggest that patients lacking SKIV2L seem more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment.
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Proteínas Portadoras/genética , ADN Helicasas/genética , Diarrea Infantil/genética , Retardo del Crecimiento Fetal/genética , Enfermedades del Cabello/genética , Codón sin Sentido , Diarrea Infantil/patología , Facies , Femenino , Retardo del Crecimiento Fetal/patología , Enfermedades del Cabello/patología , Humanos , Masculino , Mutación , FenotipoRESUMEN
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.
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ADN Helicasas/genética , Diarrea Infantil/genética , Retardo del Crecimiento Fetal/genética , Enfermedades del Cabello/genética , Mutación Missense , Diarrea Infantil/diagnóstico , Facies , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Marcadores Genéticos , Enfermedades del Cabello/diagnóstico , Humanos , Lactante , Secuenciación del ExomaRESUMEN
Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital enteropathy with seven main clinical features: intractable diarrhea of infancy, hair abnormalities, intrauterine growth restriction (IUGR), facial dysmorphism, immune dysfunction, and liver and skin abnormalities. SD/THE is caused by mutations in TTC37 or SKIV2L, two genes encoding components of the human SKI complex. To date, approximately 50 SD/THE patients have been described with a wide spectrum of mutations, and only one recurrent mutation has been identified in independent families. We present a detailed description of seven patients of Turkish origin with the same new mutation in TTC37: c.4572 G>A p.(Trp1524X). All seven patients were homozygous for this mutation and presented the typical clinical features of SD/THE, but with a milder presentation than usual. All seven patients were alive at the last follow-up. Four out of seven patients had no IUGR, and four patients never required parenteral nutrition. All patients presented a better growth rate than previously described in patients with SD/THE, with 4/7 above the 3rd percentile. The mutation is localized only forty amino acids from the end of TTC37, and as TTC37 is longer than the yeast SKI3, it is possible that a truncated protein is expressed and plays a reduced role in the SKI complex.
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Proteínas Portadoras/genética , Diarrea/congénito , Diarrea/diagnóstico , Mutación , Fenotipo , Alelos , Preescolar , Familia , Femenino , Genotipo , Humanos , Lactante , Masculino , Linaje , Hermanos , SíndromeRESUMEN
The RNA exosome is an evolutionarily conserved, ribonuclease complex that is critical for both processing and degradation of a variety of RNAs. Cofactors that associate with the RNA exosome likely dictate substrate specificity for this complex. Recently, mutations in genes encoding both structural subunits of the RNA exosome and its cofactors have been linked to human disease. Mutations in the RNA exosome genes EXOSC3 and EXOSC8 cause pontocerebellar hypoplasia type 1b (PCH1b) and type 1c (PCH1c), respectively, which are similar autosomal-recessive, neurodegenerative diseases. Mutations in the RNA exosome gene EXOSC2 cause a distinct syndrome with various tissue-specific phenotypes including retinitis pigmentosa and mild intellectual disability. Mutations in genes that encode RNA exosome cofactors also cause tissue-specific diseases with complex phenotypes. How mutations in these genes give rise to distinct, tissue-specific diseases is not clear. In this review, we discuss the role of the RNA exosome complex and its cofactors in human disease, consider the amino acid changes that have been implicated in disease, and speculate on the mechanisms by which exosome gene mutations could underlie dysfunction and disease.
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Enfermedad/genética , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Mutación , Coenzimas/genética , Complejo Multienzimático de Ribonucleasas del Exosoma/química , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Humanos , Subunidades de Proteína/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare disease linked to the loss of function of either TTC37 or SKIV2L, two components of the SKI complex. It is characterized by a combination of 9 signs (intractable diarrhea, hair abnormalities, facial dysmorphism, immune abnormalities, IUGR/SGA, liver abnormalities, skin abnormalities, congenital heart defect and platelet abnormalities). We present a comprehensive review of the management of SD/THE and tested therapeutic regimens. A review of the literature was conducted in May 2017: 29 articles and 2 abstracts were included describing a total of 80 patients, of which 40 presented with mutations of TTC37, 14 of SKIV2L. Parenteral nutrition was used in the management of 83% of the patients and weaned in 44% (mean duration of 14.97 months). Immunoglobulins were used in 33 patients, but data on efficacy was reported for 6 patients with a diminution of infection (n = 3) or diarrhea reduction (n = 2). Antibiotics (n = 11) provided no efficacy. Steroids (n = 17) and immunosuppressant drugs (n = 13) were used with little efficacy and mostly in patients with IBD-like SD/THE. Hematopoietic stem cell transplantation (HSCT) was performed in 4 patients: 2 died, for one it corrected the immune defects but not the other features and for the last one, it provided only a partial improvement. Finally, no specific diet was effective except for some contradictory reports for elemental formula. In conclusion, the management of SD/THE mainly involves parenteral nutrition and immunoglobulin supplementation. Antibiotics, steroids, immunosuppressants, and HSCT are not recommended as principle treatments since there is no evidence of efficacy.
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PURPOSE: This study was conducted to comprehensively evaluate the potential association of SKIV2L polymorphism rs429608 with age-related macular degeneration (AMD) through a meta-analysis. METHODS: We performed a literature search in EMBASE, PubMed, Web of Science, and the Chinese Biomedical Database for AMD genetic studies published before August 30, 2015. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphisms (SNPs) using fixed-effect models or random effect models according to between-study heterogeneity. Publication bias analyses were conducted using Egger's test. RESULTS: A total of five studies from published articles were included, and a total number of 2789 AMD cases and 3451 healthy controls were tested in this meta-analysis. The results demonstrated that SKIV2L rs429608 is associated with AMD under allelic model (A vs. G; OR = 0.52, 95% CI 0.44-0.62, p < 0.001), heterozygous model (AG vs. GG; OR = 0.51; 95%CI, 0.38-0.68; p < 0.001; PQ = 0.48; I2 = 0) and dominant model (AA+AG vs. GG; OR = 0.49; 95%CI 0.37-0.65; p < 0.001; PQ = 0.44; I2 = 0), but not under other genetic models. CONCLUSIONS: This meta-analysis showed that SKIV2L rs429608 was statistically associated with AMD and it might exert a protective effect on AMD. Further investigations are needed to validate the association and confirm the role of SKIV2L in AMD.
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ADN Helicasas/genética , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Alelos , Factor H de Complemento/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Oportunidad Relativa , Factores de RiesgoRESUMEN
Hepatitis B virus (HBV) is a stealth virus, minimally inducing the interferon system required for efficient induction of both innate and adaptive immune responses. However, 90% of acutely infected adults can clear the virus, suggesting the presence of other, interferon-independent pathways leading to viral clearance. Given the known ability of helicases to bind viral nucleic acids, we performed a functional screening assay to identify helicases that regulate HBV replication. We identified the superkiller viralicidic activity 2-like (SKIV2L) RNA helicase (a homolog of the Saccharomyces cerevisiae Ski2 protein) on the basis of its direct and preferential interaction with HBV X-mRNA. This interaction was essential for HBV X-mRNA degradation at the RNA exosome. The degradation of HBV X-mRNA at the RNA exosome was also mediated by HBS1L (HBS1-like translational GTPase) protein, a known component of the host RNA quality control system. We found that the redundant HBV-precore translation initiation site present at the 3'-end of HBV X-mRNA (3' precore) is translationally active. The initiation of translation from this site without a proper stop codon was identified by the non-stop-mediated RNA decay mechanism leading to its degradation. Although 3' precore is present in the five main HBV-RNA transcripts, only X-mRNA lacks the presence of an upstream start codons for large, middle, and small (L, M, and S) HBV surface proteins. These upstream codons are in-frame with 3' precore translation initiation site, blocking its translation from the other HBV-mRNA transcripts. To our knowledge, this is the first demonstration of the anti-viral function of the non-stop-mediated RNA decay mechanism.
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Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Virus de la Hepatitis B/metabolismo , Estabilidad del ARN , ARN Mensajero/metabolismo , ARN Viral/metabolismo , Transactivadores/biosíntesis , Codón Iniciador/genética , Codón Iniciador/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Células Hep G2 , Virus de la Hepatitis B/genética , Humanos , ARN Mensajero/genética , ARN Viral/genética , Transactivadores/genética , Proteínas Reguladoras y Accesorias ViralesRESUMEN
Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder that is classically associated with intractable diarrhea with an onset within the first few months of life. Herein, we investigated and reported novel mutations in two causal genes in 3 Malaysian cases. Genomic DNA was extracted from peripheral blood obtained from patients in two Malaysian Chinese families. The exons of SKIV2L and TTC37 genes were amplified and sequenced by bi-directional sequencing to identify the point mutations within the coding sequence. Three Chinese boys from two families with characteristic features and clinical course were diagnosed with THES. In family-1, two point mutations were identified in the SKIV2L gene (c.1891G>A and c.3187C>T). In family-2, a single-nucleotide duplication (c.3426dupA) was found in the TTC37 gene. These mutations cause the production of abnormal non-functional gene product leading to the clinical manifestations in the patients. We reported three point mutations, which have not been previously described in other patients with THES in SKIV2L and TTC37 genes, including one nonsense, one frameshift, and one missense mutations.
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Proteínas Portadoras/genética , ADN Helicasas/genética , Diarrea Infantil/genética , Retardo del Crecimiento Fetal/genética , Enfermedades del Cabello/genética , Pueblo Asiatico/genética , Codón sin Sentido , Diarrea Infantil/patología , Diarrea Infantil/fisiopatología , Exones , Facies , Retardo del Crecimiento Fetal/patología , Retardo del Crecimiento Fetal/fisiopatología , Mutación del Sistema de Lectura , Enfermedades del Cabello/patología , Enfermedades del Cabello/fisiopatología , Humanos , Masculino , Mutación Missense , LinajeRESUMEN
BACKGROUND: To investigate the association between age-related macular degeneration (AMD) and the polymorphisms of HIF1A, a major vascular epithelial growth factor regulator under hypoxic conditions. The associations of AMD and polymorphisms of genes CFH, SKIV2L and MYRIP were also studied. DESIGN: Prospective study. PARTICIPANTS: Eighty-seven AMD patients and 80 healthy subjects admitted to the Department of Ophthalmology at Pamukkale University Hospital, Denizli, Turkey, were included: 45 (52%) had wet type AMD, and 42 (48%) had dry type AMD. METHODS: Polymorphisms rs1061170 (CFH), rs429608 (SKIV2L), rs2679798 (MYRIP) and both rs11549465 and rs11549467 (HIF1A) were investigated in DNA isolated from peripheral blood samples of the cases and controls by dye-termination DNA sequencing. MAIN OUTCOME MEASURES: Genotype distribution of rs1061170 (CFH), rs429608 (SKIV2L), rs2679798 (MYRIP) and both rs11549465 and rs11549467 (HIF1A) in AMD cases and healthy controls; association between genotypes and AMD subtypes. RESULTS: Given the significant difference between the mean age of case and control groups (72.13 ± 5.77 vs. 62.80 ± 5.22, respectively) (P = .000), subsequent analyses were adjusted for age. We found that having at least one C allele for polymorphism rs1061170 increases AMD risk independent of age (OR = 2.42, 95% confidence interval [CI], 1.22-4.81). The ancestral T allele for polymorphism rs1061170 has a protective effect for AMD (OR = 0.53, 95% CI, 0.34-0.83). No statistically significant difference for distributions of other single nucleotide polymorphisms (SNPs) emerged between patients and healthy subjects. CONCLUSIONS: No associations appeared between HIF1A SNPs and AMD, which were studied here for the first time; however, polymorphism rs1061170 of the CFH gene is associated with AMD in our population.
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Atrofia Geográfica/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/metabolismo , Degeneración Macular Húmeda/genética , Anciano , Factor H de Complemento/genética , ADN Helicasas/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Análisis de Secuencia de ADN , Proteínas de Transporte Vesicular/genéticaRESUMEN
The RNA exosome has a key role in RNA decays and RNA quality control. In 2012, two human Mendelian diseases: syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) and Ponto-cerebellar hypoplasia type 1(PCH1) were linked to the RNA exosome or its cofactor's defect. SD/THE's main features are an intractable diarrhea of infancy associated with hair abnormalities, facial dysmorphism, intra uterine growth restriction and immune deficiency. SD/THE is caused by a defect of the SKI complex (TTC37 and SKIV2L), the cytoplasmic co-factor of the RNA exosome for mRNA degradation. PCH1's main features are atrophy of the pons and of the cerebellum, a progressive microcephaly with developmental delay and muscle atrophy secondary to spinal anterior horn cell loss. In 30-40% of patients, PCH1 is caused by a defect in EXOSC3 which encodes RRP40, a protein of the cap of the RNA exosome. Thanks to knowledge about other forms of PCH it could be assumed that the altered substrates are probably transfer RNA However, as there exists no patient with two null mutations, residual RNA exosome functionality is probably required to preserve viability. Thus, to date two very different human Mendelian diseases have been related to the dysfunctioning of the RNA exosome. It illustrates the versatility of the RNA exosome function and substrate.