共查询到20条相似文献,搜索用时 31 毫秒
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Annegret Buske Andreas Gewies Rüdiger Lehmann Klaus Rüther Bernd Algermissen Peter Nürnberg Sigrid Tinschert 《American journal of medical genetics. Part A》1999,86(4):328-330
We report a 21-year-old male with symptomatic optic glioma who does not fulfill the diagnosis of neurofibromatosis 1 (NF1) according to standard NIH criteria. Analysis of the NF1 gene revealed a recurrent mutation in exon 37 (C6792A or Y2264X). This nonsense mutation causes skipping of exon 37 during the splicing process and is predicted to result in a protein shortened by 34 amino acid residues. The mutation was detected in all tissues examined (blood lymphocytes, oral mucosa, and dermal fibroblasts). The same mutation was previously found in 3 patients with clinically confirmed NF1. To our knowledge, this is the first report of an adult patient carrying a putative (non-mosaic) NF1 gene mutation in multiple tissues but not fulfilling the NIH criteria for the clinical diagnosis of NF1. Am. J. Med. Genet. 86:328–330, 1999. 相似文献
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Eva Pros Juana Fernández‐Rodríguez Belén Canet Llúcia Benito Aurora Sánchez Ana Benavides Feliciano J. Ramos María Asunción López‐Ariztegui Gabriel Capellá Ignacio Blanco Eduard Serra Conxi Lázaro 《Human mutation》2009,30(3):454-462
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting 1:3,500 individuals. Disease expression is highly variable and complications are diverse. However, currently there is no specific treatment for the disease. NF1 is caused by mutations in the NF1 gene, approximately 2.1% of constitutional mutations identified in our population are deep intronic mutations producing the insertion of a cryptic exon into the mature mRNA. We used antisense morpholino oligomers (AMOs) to restore normal splicing in primary fibroblast and lymphocyte cell lines derived from six NF1 patients bearing three deep intronic mutations in the NF1 gene (c.288+2025T>G, c.5749+332A>G, and c.7908‐321C>G). AMOs were designed to target the newly created 5′ splice sites to prevent the incorporation of cryptic exons. Our results demonstrate that AMO treatment effectively restored normal NF1 splicing at the mRNA level for the three mutations studied in the different cell lines analyzed. We also found that AMOs had a rapid effect that lasted for several days, acting in a sequence‐specific manner and interfering with the splicing mechanism. Finally, to test whether the correction of aberrant NF1 splicing also restored neurofibromin function to wild‐type levels, we measured the amount of Ras‐GTP after AMO treatment in primary fibroblasts. The results clearly show an AMO‐dependent decrease in Ras‐GTP levels, which is consistent with the restoration of neurofibromin function. To our knowledge this is the first time that an antisense technique has been usedsuccessfully to correct NF1 mutations opening the possibility of a therapeutic strategy for this type of mutation not only for NF1 but for other genetic disorders. Hum Mutat 30, 454–462, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
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Sandie Le Guédard‐Méreuze Christel Vaché David Baux Valérie Faugère Lise Larrieu Caroline Abadie Andreas Janecke Mireille Claustres Sylvie Tuffery‐Giraud 《Human mutation》2010,31(3):347-355
Molecular diagnosis in Usher syndrome type 1 and 2 patients led to the identification of 21 sequence variations located in noncanonical positions of splice sites in MYO7A, CDH23, USH1C, and USH2A genes. To establish experimentally the splicing pattern of these substitutions, whose impact on splicing is not always predictable by available softwares, ex vivo splicing assays were performed. The branch‐point mapping strategy was also used to investigate further a putative branch‐point mutation in USH2A intron 43. Aberrant splicing was demonstrated for 16 of the 21 (76.2%) tested sequence variations. The mutations resulted more frequently in activation of a nearby cryptic splice site or use of a de novo splice site than exon skipping (37.5%). This study allowed the reclassification as splicing mutations of one silent (c.7872G>A (p.Glu2624Glu) in CDH23) and four missense mutations (c.2993G>A (p.Arg998Lys) in USH2A, c.592G>A (p.Ala198Thr), c.3503G>C [p.Arg1168Pro], c.5944G>A (p.Gly1982Arg) in MYO7A), whereas it provided clues about a role in structure/function in four other cases: c.802G>A (p.Gly268Arg), c.653T>A (p.Val218Glu) (USH2A), and c.397C>T (p.His133Tyr), c.3502C>T (p.Arg1168Trp) (MYO7A). Our data provide insights into the contribution of splicing mutations in Usher genes and illustrate the need to define accurately their splicing outcome for diagnostic purposes. Hum Mutat 31:1–9, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
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Logan C. Walker Phillip J. Whiley Fergus J. Couch Daniel J. Farrugia Sue Healey Diana M. Eccles Feng Lin Samantha A. Butler Sheila A. Goff Bryony A. Thompson Sunil R. Lakhani Leonard M. Da Silva Sean V. Tavtigian David E. Goldgar Melissa A. Brown Amanda B. Spurdle 《Human mutation》2010,31(6):E1484-E1505
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Exon‐Specific U1s Correct SPINK5 Exon 11 Skipping Caused by a Synonymous Substitution that Affects a Bifunctional Splicing Regulatory Element
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The c.891C>T synonymous transition in SPINK5 induces exon 11 (E11) skipping and causes Netherton syndrome (NS). Using a specific RNA–protein interaction assay followed by mass spectrometry analysis along with silencing and overexpression of splicing factors, we showed that this mutation affects an exonic bifunctional splicing regulatory element composed by two partially overlapping silencer and enhancer sequences, recognized by hnRNPA1 and Tra2β splicing factors, respectively. The C‐to‐T substitution concomitantly increases hnRNPA1 and weakens Tra2β‐binding sites, leading to pathological E11 skipping. In hybrid minigenes, exon‐specific U1 small nuclear RNAs (ExSpe U1s) that target by complementarity intronic sequences downstream of the donor splice site rescued the E11 skipping defect caused by the c.891C>T mutation. ExSpe U1 lentiviral‐mediated transduction of primary NS keratinocytes from a patient bearing the mutation recovered the correct full‐length SPINK5 mRNA and the corresponding functional lympho‐epithelial Kazal‐type related inhibitor protein in a dose‐dependent manner. This study documents the reliability of a mutation‐specific, ExSpe U1‐based, splicing therapy for a relatively large subset of European NS patients. Usage of ExSpe U1 may represent a general approach for correction of splicing defects affecting skin disease genes. 相似文献
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Gillian I. Rice Martin A.M. Reijns Stephanie R. Coffin Gabriella M.A. Forte Beverley H. Anderson Marcin Szynkiewicz Hannah Gornall David Gent Andrea Leitch Maria P. Botella Elisa Fazzi Blanca Gener Lieven Lagae Ivana Olivieri Simona Orcesi Kathryn J. Swoboda Fred W. Perrino Andrew P. Jackson Yanick J. Crow 《Human mutation》2013,34(8):1066-1070
Aicardi–Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full‐length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families. 相似文献
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Virginie Kergourlay Ghadi Raï Gaëlle Blandin David Salgado Christophe Béroud Nicolas Lévy Martin Krahn Marc Bartoli 《Human mutation》2014,35(12):1532-1541
Missense, iso‐semantic, and intronic mutations are challenging for interpretation, in particular for their impact in mRNA. Various tools such as the Human Splicing Finder (HSF) system could be used to predict the impact on splicing; however, no diagnosis result could rely on predictions alone, but requires functional testing. Here, we report an in vitro approach to study the impact of DYSF mutations on splicing. It was evaluated on a series of 45 DYSF mutations, both intronic and exonic. We confirmed splicing alterations for all intronic mutations localized in 5′ or 3′ splice sites. Then, we showed that DYSF missense mutations could also result in splicing defects: mutations c.463G>A and c.2641A>C abolished ESEs and led to exon skipping; mutations c.565C>G and c.1555G>A disrupted Exonic Splicing Enhancer (ESE), while concomitantly creating new 5′ or 3′ splice site leading to exonic out of frame deletions. We demonstrated that 20% of DYSF missense mutations have a strong impact on splicing. This minigene strategy is an efficient tool for the detection of splicing defects in dysferlinopathies, which could allow for a better comprehension of splicing defects due to mutations and could improve prediction tools evaluating splicing defects. 相似文献
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Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). 总被引:2,自引:0,他引:2
A Buske A Gewies R Lehmann K Rüther B Algermissen P Nürnberg S Tinschert 《American journal of medical genetics》1999,86(4):328-330
We report a 21-year-old male with symptomatic optic glioma who does not fulfill the diagnosis of neurofibromatosis 1 (NF1) according to standard NIH criteria. Analysis of the NF1 gene revealed a recurrent mutation in exon 37 (C6792A or Y2264X). This nonsense mutation causes skipping of exon 37 during the splicing process and is predicted to result in a protein shortened by 34 amino acid residues. The mutation was detected in all tissues examined (blood lymphocytes, oral mucosa, and dermal fibroblasts). The same mutation was previously found in 3 patients with clinically confirmed NF1. To our knowledge, this is the first report of an adult patient carrying a putative (non-mosaic) NF1 gene mutation in multiple tissues but not fulfilling the NIH criteria for the clinical diagnosis of NF1. 相似文献
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Hermansky–Pudlak syndrome type 2: Aberrant pre‐mRNA splicing and mislocalization of granule proteins in neutrophils
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Martin de Boer Karin van Leeuwen Judy Geissler Floris van Alphen Esther de Vries Martijn van der Kuip Suzanne W.J. Terheggen Hans Janssen Timo K. van den Berg Alexander B. Meijer Dirk Roos Taco W. Kuijpers 《Human mutation》2017,38(10):1402-1411
Hermansky–Pudlak syndrome type 2 (HPS2) is a syndrome caused by mutations in the beta‐3A subunit of the adaptor protein (AP)‐3 complex (AP3B1 gene). We describe five unreported cases with four novel mutations, one of which caused aberrant pre‐mRNA splicing. A point mutation c.2702C>G in exon 23 of the AP3B1 gene caused deletion of 112 bp in the mRNA in two siblings. This mutation activates a cryptic donor splice site that overrules the wild‐type donor splice site of this exon. Three other novel mutations in AP3B1 were identified, that is, a nonsense mutation c.716G>A (p.Trp239Ter), a 1‐bp and a 4‐bp deletion c.177delA and c.1839_1842delTAGA, respectively, both causing frameshift and premature termination of translation. Mass spectrometry in four of these HPS2 patients demonstrated the (near) absence of all AP‐3 complex subunits. Immunoelectron microscopy on the neutrophils of two of these patients showed abnormal granule formation. We found clear mislocalization of myeloperoxidase in the neutrophils even though the content of this protein but not the activity seemed to be present at normal levels. In sum, HPS2 is the result of the absence of the entire AP‐3 complex, which results in severe neutropenia with a defect in granule formation as the major hematological finding. 相似文献
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Fofanova OV Evgrafov OV Polyakov AV Peterkova VA Dedov II 《Bulletin of experimental biology and medicine》2006,141(3):347-352
Children, residents of the Russian Federation, with congenital isolated growth hormone deficiency, were screened for mutations
of GH-1 gene, the main gene of this deficiency. Twenty-eight children from 26 families with total congenital isolated growth hormone
deficiency were examined. Direct sequencing of GH-1 detected five splicing mutations in intron 2, intron 3, and exon 4, two of them were never described previously. Three dominant
negative mutations of GH-1 splicing, the basis for autosomal dominant isolated growth hormone deficiency (type II), are presented: IVS2 −2A>T, IVS3
+2T>C, and IVS3 +1G<A. GH-1 is the main gene of type II isolated growth hormone deficiency in patients living in the Russian Federation. All detected
mutations of GH-1 impair splicing processes, which distinguishes them from mutations in other forms of isolated growth hormone deficiency.
The detected variety of GH-1 splicing mutations attests to allele genetic heterogeneity of this pathology. The “hot spot” of mutations is 5′-donor splicing
site of GH-1 intron 3, while IVS3 +1G>A mutation can be regarded as the most incident in type II isolated growth hormone deficiency in
the Russian population.
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Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 3, pp. 324–329, March, 2006 相似文献
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Wimmer K Roca X Beiglböck H Callens T Etzler J Rao AR Krainer AR Fonatsch C Messiaen L 《Human mutation》2007,28(6):599-612
We describe 94 pathogenic NF1 gene alterations in a cohort of 97 Austrian neurofibromatosis type 1 patients meeting the NIH criteria. All mutations were fully characterized at the genomic and mRNA levels. Over half of the patients carried novel mutations, and only a quarter carried recurrent minor-lesion mutations at 16 mutational warm spots. The remaining patients carried NF1 microdeletions (7%) and rare recurring mutations. Thirty-six of the mutations (38%) altered pre-mRNA splicing, and fall into five groups: exon skipping resulting from mutations at authentic splice sites (type I), cryptic exon inclusion caused by deep intronic mutations (type II), creation of de novo splice sites causing loss of exonic sequences (type III), activation of cryptic splice sites upon authentic splice-site disruption (type IV), and exonic sequence alterations causing exon skipping (type V). Extensive in silico analyses of 37 NF1 exons and surrounding intronic sequences suggested that the availability of a cryptic splice site combined with a strong natural upstream 3' splice site (3'ss)is the main determinant of cryptic splice-site activation upon 5' splice-site disruption. Furthermore, the exonic sequences downstream of exonic cryptic 5' splice sites (5'ss) resemble intronic more than exonic sequences with respect to exonic splicing enhancer and silencer density, helping to distinguish between exonic cryptic and pseudo 5'ss. This study provides valuable predictors for the splicing pathway used upon 5'ss mutation, and underscores the importance of using RNA-based techniques, together with methods to identify microdeletions and intragenic copy-number changes, for effective and reliable NF1 mutation detection. 相似文献
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