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1.
Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms 总被引:13,自引:0,他引:13
Klamt B; Koziell A; Poulat F; Wieacker P; Scambler P; Berta P; Gessler M 《Human molecular genetics》1998,7(4):709-714
The Wilms' tumor gene WT1 plays a key role in genitourinary development and
subsequent normal function. Homozygous mutations of WT1 can be found in
approximately 15% of Wilms' tumors. Furthermore, somatic heterozygous loss
of WT1 is known to lead to cryptorchidism and hypospadias in males. A much
more severe phenotype is seen in patients with Denys-Drash syndrome which
results from heterozygous dominant- negative mutations of the gene.
Characteristic features are mesangial sclerosis with early kidney failure,
varying degrees of gonadal dysgenesis and high risk of Wilms' tumors. Here
we show that a related disease, Frasier syndrome, characterized by focal
glomerular sclerosis, delayed kidney failure and complete gonadal
dysgenesis, is probably caused by specific intronic point mutations of WT1
that preferentially affect a CpG dinucleotide. Disruption of alternative
splicing at the exon 9 splice donor site prevents synthesis of the usually
more abundant WT1 +KTS isoform from the mutant allele. In contrast to
Denys- Drash syndrome, no mutant protein is produced. The splice mutation
leads to an imbalance of WT1 isoforms in vivo , as detected by RT-PCR on
streak gonadal tissue. Thus, WT1 isoforms must have quite different
functions, and the pathology of Frasier syndrome suggests that especially
gonadal development may be particularly sensitive to imbalance or relative
underrepresentation of the WT1 +KTS isoform.
相似文献
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We report new mutations in exon 9 of the WT1 gene that did not alter the ratio of +/- KTS splice isoforms in two unrelated patients with Frasier syndrome (FS). The mutation of intron 9 inducing defective alternative splicing was reported to be responsible for this syndrome. The mutations found in our cases occurred in the same exon of the WT1 gene as detected in Denys-Drash syndrome (DDS) and could not be explained by the previously proposed mechanism. The results suggest that the two syndromes originate from the same WT1 gene abnormality. From a molecular biological point of view, we concluded that the two diseases were not separable, and that FS should be included as an atypical form of DDS. 相似文献
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Identification of a DNA-binding site and transcriptional target for the EWS-WT1(+KTS) oncoprotein 总被引:2,自引:0,他引:2
Reynolds PA Smolen GA Palmer RE Sgroi D Yajnik V Gerald WL Haber DA 《Genes & development》2003,17(17):2094-2107
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Motoko Tsuruta Hiroshi Mitsubuchi S. Mardy Yuichi Miura Yumi Hayashida Akihiko Kinugasa Takateru Ishitsu Ichiro Matsuda Y. Indo 《Journal of human genetics》1998,43(2):91-100
The E2 gene of the branched-chain α-keto acid dehydrogenase (BCKDH) complex was studied at the molecular level in three patients
with intermittent maple syrup urine disease (MSUD). All three patients had higher BCKDH activity than did those with the classical
phenotype. In the first patient, a single base substitution from A to G in intron 8 created a new 5′ splice site and caused
an insertion of 126 nucleotides between exons 8 and 9 by activating an upstream cryptic 3′ splice site in the same intron.
The predicted mRNA encoded a truncated protein with 282 amino acids including 4 novel ones at the carboxyl terminus, compared
with the normal protein with 421 amino acids. In vitro, the region from the patient but not from a normal control was recognized
and was recovered as a novel exon, indicating that the single substitution was responsible for incorporation of the region
into mRNA. This mutation probably supports an exon definition model in which the spliceosome recognizes a 3′ splice site and
then scans downstream for an acceptable 5′ splice site, thereby defining an exon. The second patient was homozygous for a
G to T transversion at nucleotide 1463 in exon 11, which predicted a substitution of the termination codon by a leucine residue
and the addition of 7 extra amino acids at the carboxyl terminus. For each mutation, these two patients were homozygous and
their parents were heterozygous. The third patient was a compound heterozygote for a C to G transversion at nucleotide 309
in exon 4 and a G to A transition at nucleotide 1165 in exon 9, causing an Ile-to-Met substitution at amino acid 37 and a
Gly-to-Ser substitution at amino acid 323, respectively. Taken together, these results indicate that the molecular basis of
intermittent phenotype MSUD in some patients can be due to mutations in the E2 gene, giving rise to a low but significant residual activity of the BCKDH complex.
Received: October 29, 1997 / Accepted: November 27, 1997 相似文献
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Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome? 总被引:6,自引:0,他引:6
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H Kikuchi A Takata Y Akasaka R Fukuzawa H Yoneyama Y Kurosawa M Honda Y Kamiyama J Hata 《Journal of medical genetics》1998,35(1):45-48
The WT1 gene, one of the genes responsible for Wilms tumour, is thought to play a crucial role in the development of the kidneys and gonads. This gene encodes four protein isoforms resulting from two alternative splicing sites, one of which involves inclusion or exclusion of lysine, threonine, and serine (KTS) between the third and fourth zinc finger domains. WT1 is virtually always mutationally inactivated in patients with Denys-Drash syndrome. We analysed WT1 in eight patients who had been diagnosed as having this syndrome, and identified five previously unknown mutations affecting splicing donor sites of intron 9. These mutations affect alternative splicing. The isoforms retaining KTS are not produced. The clinical features of the patients with these intronic mutations were consistent with those of Frasier syndrome, characterised by a more slowly progressive nephropathy than Denys-Drash syndrome, associated streak gonads, and no Wilms tumour development. Our results indicate that WT1 isoforms, including/excluding KTS, have different functions in tumorigenesis and organogenesis of the kidneys and gonads. 相似文献
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Ralf W. Lbbert Gabi Klemm Hans-Peter Grüttner Dieter Harms Andreas Winterpacht Bernhard U. Zabel 《Genes, chromosomes & cancer》1998,21(4):347-350
About 5–10% of sporadic Wilms' tumors (WT) are associated with mutations in the Wilms' tumor 1 gene (WT1). More than 90% of patients with Denys-Drash syndrome (DDS; characterized by renal nephropathy, gonadal anomaly, and predisposition to WT) show constitutional intragenic WT1 mutations. We describe a novel WT1 stop-mutation in exon 2. This heterozygous germline mutation was detected in a one-year-old girl who was bilaterally affected with Wilms' tumor but without any other clinical manifestations of DDS. The C-to-A transversion is predicted to result in a polypeptide comprising only the first 165 amino acids of the WT1 protein. Loss of heterozygosity (LOH) studies comparing tumor DNA with lymphocyte DNA revealed LOH for the entire short arm of chromosome 11 in tumor tissue. In addition to the chromosome 11 lesions, the tumor showed a seemingly balanced chromosomal translocation t(7;12) (p22;q22) as the only visible cytogenetic aberration. Genes Chromosomes Cancer 21:347–350, 1998. © 1998 Wiley-Liss, Inc. 相似文献
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Ramos-Trujillo E González-Acosta H Flores C García-Nieto V Guillén E Gracia S Vicente C Espinosa L Maseda MA Santos F Camacho JA Claverie-Martín F 《Journal of human genetics》2007,52(3):255-261
Mutations in the voltage-gated chloride/proton antiporter ClC-5 gene, CLCN5, are associated with Dent’s disease, an X-linked renal tubulopathy. Our interest is to identify and characterize disease-causing
CLCN5 mutations, especially those that alter the splicing of the pre-mRNA. We analyzed the CLCN5 gene from nine unrelated Spanish Dent’s disease patients and their relatives by DNA sequencing. Pre-mRNA splicing analysis
was performed by RT-PCR. Seven new mutations were identified, consisting of three missense mutations (C219R, F273L, and W547G),
one splice-site mutation (IVS-2A > G), one deletion (976delG), and two non-sense mutations (Y140X and W314X). We found that
missense mutation W547G also led to increased expression of a new alternative isoform lacking exons 10 and 11 that was expressed
in several human tissues. In addition, we describe another novel CLCN5 splicing variant lacking exon 11 alone, which was expressed only in human skeletal muscle. We conclude that missense mutation
W547G can also alter the expression levels of a CLCN5 mRNA splicing variant. This type of mutation has not been previously described in the CLCN5 gene. Our results support the importance of a routine analysis at the pre-mRNA level of mutations that are commonly assumed
to cause single amino acids alterations. 相似文献
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T. C. Hunter S. B. Melancon L. Dallaire S. Taft T. R. Skopek R. J. Albertini J. P. O'Neill 《Somatic Cell and Molecular Genetics》1996,22(2):145-150
We have used peripheral blood T-lymphocyte cultures to analyze the hprt mutation in two Lesch-Nyhan syndrome males who are
cousins and to confirm the carrier status of female members of the family. Both cDNA and genomic DNA sequencing studies show
that this patient carries a hitherto undescribed single base deletion in the exon 5 donor splice site sequence (15:+1, δG,
base number 31635). The largest cDNA product contained all nine hprt exons plus an insertion of 66 bases of intron 5, consistent
with the use of a cryptic splice site in intron 5 (aag67/gtaagc). This splicing error would result in a chain terminating codon immediately after exon 5 (15:2–4, taa) and predicts
a polypeptide of 133 amino acids. This loss of the normal splice donor site also results in multiple hprt mRNA species, combining
the use of the cryptic splice site in intron 5 and splicing errors involving exons 2–6. In addition to defining a new Lesch-Nyhan
mutation (hprtHenryville), these results provide insight into aberrant splicing of hprt mRNA in T-lymphocytes. 相似文献
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Kevin T. Booth Hela Azaiez Kimia Kahrizi Donghong Wang Yuzhou Zhang Kathy Frees Carla Nishimura Hossein Najmabadi Richard J Smith 《Human mutation》2018,39(3):433-440
Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness‐associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5‐related deafness. In five families with postlingual progressive autosomal dominant non‐syndromic hearing loss, we employed two next‐generation sequencing platforms—OtoSCOPE and whole exome sequencing—followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini‐genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5‐related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing. 相似文献
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The ETFDH c.158A>G Variation Disrupts the Balanced Interplay of ESE‐ and ESS‐Binding Proteins thereby Causing Missplicing and Multiple Acyl‐CoA Dehydrogenation Deficiency
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Rikke K. J. Olsen Sabrina Brøner Rugivan Sabaratnam Thomas K. Doktor Henriette S. Andersen Gitte H. Bruun Birthe Gahrn Vibeke Stenbroen Simon E. Olpin Angus Dobbie Niels Gregersen Brage S. Andresen 《Human mutation》2014,35(1):86-95
Multiple acyl‐CoA dehydrogenation deficiency is a disorder of fatty acid and amino acid oxidation caused by defects of electron transfer flavoprotein (ETF) or its dehydrogenase (ETFDH). A clear relationship between genotype and phenotype makes genotyping of patients important not only diagnostically but also for prognosis and for assessment of treatment. In the present study, we show that a predicted benign ETFDH missense variation (c.158A>G/p.Lys53Arg) in exon 2 causes exon skipping and degradation of ETFDH protein in patient samples. Using splicing reporter minigenes and RNA pull‐down of nuclear proteins, we show that the c.158A>G variation increases the strength of a preexisting exonic splicing silencer (ESS) motif UAGGGA. This ESS motif binds splice inhibitory hnRNP A1, hnRNP A2/B1, and hnRNP H proteins. Binding of these inhibitory proteins prevents binding of the positive splicing regulatory SRSF1 and SRSF5 proteins to nearby and overlapping exonic splicing enhancer elements and this causes exon skipping. We further suggest that binding of hnRNP proteins to UAGGGA is increased by triggering synergistic hnRNP H binding to GGG triplets located upstream and downsteam of the UAGGGA motif. A number of disease‐causing exonic elements that induce exon skipping in other genes have a similar architecture as the one in ETFDH exon 2. 相似文献