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Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease.

ABSTRACT: While a base substitution in intron 4 of GLA (IVS4+919G>A) that causes aberrant alternative splicing resulting in Fabry disease has been reported, its molecular mechanism remains unclear. Here we reported that upon IVS4+919G>A transversion, H3K36me3 was enriched across the alternatively spliced region. PSIP1, an adapter of H3K36me3, together with Hsp70 and NONO were recruited and formed a complex with SF2/ASF and SRp20, which further promoted GLA splicing. Amiloride, a splicing regulator in cancer cells, could reverse aberrant histone modification patterns and disrupt the association of splicing complex with GLA. It could also reverse aberrant GLA splicing in a PP1-dependant manner. Our findings revealed the alternative splicing mechanism of GLA (IVS4+919G>A), and a potential treatment for this specific genetic type of Fabry disease by amiloride in the future.

SUBMITTER: Chang WH

PROVIDER: S-EPMC5400244 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease.

Chang Wen-Hsin WH Niu Dau-Ming DM Lu Chi-Yu CY Lin Shyr-Yi SY Liu Ta-Chih TC Chang Jan-Gowth JG

PloS one 20170421 4

While a base substitution in intron 4 of GLA (IVS4+919G>A) that causes aberrant alternative splicing resulting in Fabry disease has been reported, its molecular mechanism remains unclear. Here we reported that upon IVS4+919G>A transversion, H3K36me3 was enriched across the alternatively spliced region. PSIP1, an adapter of H3K36me3, together with Hsp70 and NONO were recruited and formed a complex with SF2/ASF and SRp20, which further promoted GLA splicing. Amiloride, a splicing regulator in canc ...[more]

PMID: 28430823

Similar Datasets

Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A).

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| S-EPMC2769558 | biostudies-literature

Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A).

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| S-EPMC3717460 | biostudies-literature

Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset Fabry mutation (IVS4?+?919G?>?A).

Project description:BACKGROUND: In Taiwan, DNA-based newborn screening showed a surprisingly high incidence of a cardiac Fabry mutation (IVS4?+?919G?>?A). The prevalence of this mutation is too high to be believed that it is a real pathogenic mutation. The purpose of this study is to identify the cardiac pathologic characteristics in patients with left ventricular hypertrophy and this mutation METHODS AND RESULTS: Endomyocardial biopsies were obtained in 22 patients (Median age: 61, males: 17; females: 5) with left ventricular hypertrophy and the IVS4?+?919G?>?A mutation; five patients had not received enzyme replacement therapy (ERT) before biopsy, while the other 17 patients had received ERT from 8 months to 51 months. Except for three patients who had received ERT for more than 3 years, all other patients showed significant pathological change and globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. In contrast to classical Fabry patients, no Gb3 accumulation was found in the capillary endothelial cells of any of our patients. Fourteen patients (63.6%) were found to have myofibrillolysis. CONCLUSIONS: All of the untreated and most of the treated IVS4?+?919G?>?A patients showed typical pathological changes of Fabry disease in their cardiomyocytes. No endothelial accumulation of Gb3 was found, which is similar to the findings of several previous reports regarding later-onset Fabry disease. This result highly suggests that the IVS4?+?919G?>?A is a real pathogenic later-onset Fabry mutation.

| S-EPMC4100491 | biostudies-literature

A comparison of central nervous system involvement in patients with classical Fabry disease or the later-onset subtype with the IVS4+919G>A mutation.

Project description:Patients with the later-onset IVS4+919G>A (IVS4) Fabry mutation are known to have positive central nervous system involvement compared with age- and sex-matched controls. This study compares central nervous system manifestations in patients with the IVS4 mutation or classical Fabry mutations.This was a retrospective analysis of magnetic resonance imaging (MRI) data from Taiwanese patients enrolled in the Fabry Outcome Survey (sponsored by Shire; data extracted March 2015).Twenty-five IVS4 (19 males) and 12 (four males) classical Fabry patients underwent MRI at a median (range) age of 60.7 (45.0-70.4) and 43.0 (18.0-61.4) years, respectively. All patients received agalsidase alfa enzyme replacement therapy; two (16.7%) classical Fabry patients underwent MRI before treatment start. The pulvinar sign occurred in eight (32.0%; seven males) IVS4 and six (50.0%; three males) classical Fabry patients. Infarction occurred in eight (32.0%) IVS4 and four (33.3%) classical Fabry patients. Fazekas scores of 0, 1, 2, and 3 were found for 15 (60.0%), seven (28.0%), two (8.0%), and one (4.0%) of the IVS4 patients and for six (50.0%), four (33.3%), two (16.7%), and 0 classical Fabry patients, respectively. Abnormal height bifurcation of the basilar artery was observed in 40.0% of IVS4 and 58.3% of classical Fabry patients; abnormal laterality was observed in 4.0% of IVS4 and 16.7% of classical Fabry patients. Median (range) basilar artery diameter was 2.7 (1.4-4.0) mm in IVS4 and 3.2 (2.3-4.7) mm in classical Fabry patients (P?=?0.0293); vascular stenosis was noted in 8.3% of IVS4 patients but in no classical Fabry patients.A similar range of MRI findings was found for both IVS4 and classical Fabry patients. Notably, basilar artery diameter was larger in classical Fabry patients than IVS4 patients.

| S-EPMC5294737 | biostudies-literature

Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation.

Project description:RationaleA high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown.ObjectiveUsing FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC.Results and methodsThe iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients' sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs.ConclusionOur data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation.

| S-EPMC5349979 | biostudies-literature

Fabry disease: incidence of the common later-onset ?-galactosidase A IVS4+919G?A mutation in Taiwanese newborns--superiority of DNA-based to enzyme-based newborn screening for common mutations.

Project description:Fabry disease is a panethnic, X-linked, inborn error of glycosphingolipid metabolism resulting from mutations in the ?-galactosidase A gene (GLA) that lead to the deficient activity of the lysosomal enzyme, ?-galactosidase A (?-Gal A). Affected males with no ?-Gal A activity have the early-onset classic phenotype, whereas those with residual activity present with the later-onset subtype. Recently, we reported that newborn enzyme-based screening using dried blood spots (DBS) in Taiwan revealed a high incidence of newborn males who had the GLA c.936+919G?A (IVS4+919G?A) mutation. This lesion causes cryptic splicing, markedly reducing the amount of wild-type GLA mRNA, and has been found in males with the later-onset Fabry phenotype, manifesting as cardiac, renal and/or cerebrovascular disease. To more accurately determine the incidence of the IVS4+919G?A mutation, 20,063 consecutive newborns were screened by a deoxyribonucleic acid (DNA)-based assay. Of the 10,499 males, 12 (1/875) and 24 of the 9,564 females (1/399) had the mutation. On the basis of these frequencies, the previous newborn enzyme-based DBS screening (cutoff: <30% of the normal mean) only identified 67% and 17% of mutation-positive males and females, respectively. The mean DBS ?-Gal A activities in the mutation-positive males and females were 23% (1.54 U) and 55% (3.63 U) of normal mean male/female values, respectively. These studies confirm the high incidence of the IVS4+919G?A mutation in the Taiwanese population and indicate that its detectability by enzyme-based DBS screening is unreliable, especially in females. These studies emphasize the superiority of DNA-based newborn screening for common mutations, particularly for X-linked diseases.

| S-EPMC3409276 | biostudies-literature

Fabry disease due to D313Y and novel GLA mutations.

Project description:ObjectivesOur aim is to report four novel ?-gal A gene (GLA) mutations resulting in Fabry disease (FD) and provide evidence of pathogenicity of the D313Y mutation regarding which contradictory data have been presented in the literature.Setting and participantsTwenty-five family members of nine unrelated patients with definite FD diagnosis, 10 clinically suspected cases and 18 members of their families were included in this polycentric cohort study.Primary and secondary outcome measuresGenotyping and measurement of lyso-Gb3 was performed in all individuals. The ?-Gal A activity was measured in all men as well as plasma and urine Gb3 concentration in selected cases. Optical and electron microscopy was performed in kidney biopsies of selected patients. All the above were evaluated in parallel with the clinical data of the patients.ResultsFourteen new cases of FD were recognised, four of which were carrying already described GLA mutations. Four novel GLA mutations, namely c.835C>T, c.280T>A, c.924A>C and c.511G>A, resulting in a classic FD phenotype were identified. Moreover, FD was definitely diagnosed in five patients carrying the D313Y mutation. Eight D313Y carriers were presenting signs of FD despite not fulfilling the criteria of the disease, two had no FD signs and two others were apparently healthy.ConclusionsFour novel GLA pathogenic mutations are reported and evidence of pathogenicity of the D313Y mutation is provided. It seems that the D313Y mutation is related to a later-onset milder phenotype than the typical phenotype with normal lysoGb3 concentration. Our study underlines the significance of family member genotyping and newborn screening to avoid misdiagnoses and crucial delays in diagnosis and treatment of the disease.

| S-EPMC5640077 | biostudies-literature

Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease.

Project description:Fabry disease (FD) is a rare and underdiagnosed X-linked disorder resulting from the deficient activity of the lysosomal hydrolase ?-galactosidase A, which leads to storage of complex glycosphingolipids inside of lysosomes in critical organs and tissues, impairing their functions and consequently resulting in a progressive multisystem disease. FD is caused by mutations in the GLA gene, and only 4.6% of described mutations are located in the splice site regions. RNA splicing is an essential step to the formation of functional proteins, and mutations in splice site regions can cause formation of aberrant transcripts leading to disease. Here we report a novel GLA insertion at position c.801+3 in intron 5 (c.801+2_801+3insT) in a Brazilian family with suspicion of FD. The index case, a 46-year-old male, presented undetectable ?-galactosidase A activity. Analysis of blood cDNA found two aberrant GLA transcripts. In the first transcript, a novel donor splice site was created promoting formation of an intron inclusion with 37 bp. The splice site was not recognized in the second transcript and the intron 5 was not excised. The wild-type transcript was not formed and both aberrant transcripts lead to a premature stop codon. Despite not being in the canonical site, this new mutation disrupts existing 5' splice site and produces two aberrant transcripts leading to FD.

| S-EPMC6777637 | biostudies-literature

Functional evaluation of a novel GLA causative mutation in Fabry disease.

Project description:BackgroundFabry disease (FD), a rare X-linked α-galactosidase A (GLA) deficiency, resulting in progressive lysosomal accumulation of globotriaosylceramide in a variety of cell types. More and more disease-causing mutations in GLA have been identified in FD due to the advancement of molecular diagnostic tools. We found a novel mutation in a Chinese family with predominant Fabry's disease nephropathy.MethodsAll coding regions and exon-intron splice junctions of the GLA gene were sequenced to find sequence variations. We evaluated the impact on the GLA protein by analysis of the GLA mRNA, by sequential analysis and homology modeling, and by site-directed mutagenesis and in vitro expression studies.ResultsWe identified a novel heterozygous missense mutation c.280T>C in our patient with variable phenotypic presentations of renal involvement. The novel GLA variant results in low expression of GLA mRNAs, impaired or loss of the disulfate bridge structure of wild-type GLA, reduced GLA activity and defected nuclear shape in the GFP-GLA-MT transfected HEK293T cells.ConclusionA novel GLA missense mutation, c.280T>C (Cys94Arg), was found in a Chinese family with predominant renal manifestations of FD. Our study reveals the pathogenesis of c.280T>C mutation to FD and provides scientific foundation for accurate diagnosis and precise medical intervention for FD.

| S-EPMC6732343 | biostudies-literature

Double-target Antisense U1snRNAs Correct Mis-splicing Due to c.639+861C>T and c.639+919G>A GLA Deep Intronic Mutations.

Project description:Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of the ?-galactosidase A (?-Gal A) enzyme, which is encoded by the GLA gene. GLA transcription in humans produces a major mRNA encoding ?-Gal A and a minor mRNA of unknown function, which retains a 57-nucleotide-long cryptic exon between exons 4 and 5, bearing a premature termination codon. NM_000169.2:c.639+861C>T and NM_000169.2:c.639+919G>A GLA deep intronic mutations have been described to cause Fabry disease by inducing overexpression of the alternatively spliced mRNA, along with a dramatic decrease in the major one. Here, we built a wild-type GLA minigene and two minigenes that carry mutations c.639+861C>T and c.639+919G>A. Once transfected into cells, the minigenes recapitulate the molecular patterns observed in patients, at the mRNA, protein, and enzymatic level. We constructed a set of specific double-target U1asRNAs to correct c.639+861C>T and c.639+919G>A GLA mutations. Efficacy of U1asRNAs in inducing the skipping of the cryptic exon was evaluated upon their transient co-transfection with the minigenes in COS-1 cells, by real-time polymerase chain reaction (PCR), western blot analysis, and ?-Gal A enzyme assay. We identified a set of U1asRNAs that efficiently restored ?-Gal A enzyme activity and the correct splicing pathways in reporter minigenes. We also identified a unique U1asRNA correcting both mutations as efficently as the mutation-specific U1asRNAs. Our study proves that an exon skipping-based approach recovering ?-Gal A activity in the c.639+861C>T and c.639+919G>A GLA mutations is active.

| S-EPMC5095687 | biostudies-literature

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