The Experts below are selected from a list of 402 Experts worldwide ranked by ideXlab platform
Susan A Slaugenhaupt - One of the best experts on this subject based on the ideXlab platform.
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familial dysautonomia history genotype phenotype and translational research
2017Co-Authors: Lucy Norcliffekaufmann, Susan A Slaugenhaupt, Horacio KaufmannAbstract:Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.
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Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
2011Co-Authors: Felicia B Axelrod, Gabrielle Goldvon Simson, James Mull, Maire Leyne, Horacio Kaufmann, Leonard Liebes, Sandra Mendoza, Lucy Norcliffe-kaufmann, Susan A SlaugenhauptAbstract:Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients.
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kinetin in familial dysautonomia carriers implications for a new therapeutic strategy targeting mrna splicing
2009Co-Authors: Gabrielle Goldvon Simson, Judith D Goldberg, Linda Rolnitzky, James Mull, Maire Leyne, Andrei Voustianiouk, Susan A Slaugenhaupt, Felicia B AxelrodAbstract:Familial dysautonomia (FD) is caused by an intronic splice mutation in the IκB kinase–associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IκB kinase–associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetin's therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed.
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loss of mouse IKBKAP a subunit of elongator leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP
2009Co-Authors: Yei-tsung Chen, James Mull, Maire Leyne, Matthew M Hims, Lijuan Liu, Ranjit S Shetty, Susan A SlaugenhauptAbstract:Familial dysautonomia (FD), a devastating hereditary sensory and autonomic neuropathy, results from an intronic mutation in the IKBKAP gene that disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP) in the nervous system. To better understand the roles of IKAP in vivo, an IKBKAP knockout mouse model was created. Results from our study show that ablating IKBKAP leads to embryonic lethality, with no homozygous IKBKAP knockout (IKBKAP−/−) embryos surviving beyond 12.5 days postcoitum. Morphological analyses of the IKBKAP−/− conceptus at different stages revealed abnormalities in both the visceral yolk sac and the embryo, including stunted extraembryonic blood vessel formation, delayed entry into midgastrulation, disoriented dorsal primitive neural alignment, and failure to establish the embryonic vascular system. Further, we demonstrate downregulation of several genes that are important for neurulation and vascular development in the IKBKAP−/− embryos and show that this correlates with a defect in transcriptional elongation-coupled histone acetylation. Finally, we show that the embryonic lethality resulting from IKBKAP ablation can be rescued by a human IKBKAP transgene. For the first time, we demonstrate that IKAP is crucial for both vascular and neural development during embryogenesis and that protein function is conserved between mouse and human.
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IKBKAP mrna in peripheral blood leukocytes a molecular marker of gene expression and splicing in familial dysautonomia
2008Co-Authors: Gabrielle Goldvon Simson, Judith D Goldberg, Linda Rolnitzky, James Mull, Maire Leyne, Felicia B Axelrod, Dena Berlin, Susan A SlaugenhauptAbstract:The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IκB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IκB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.
Maire Leyne - One of the best experts on this subject based on the ideXlab platform.
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Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
2011Co-Authors: Felicia B Axelrod, Gabrielle Goldvon Simson, James Mull, Maire Leyne, Horacio Kaufmann, Leonard Liebes, Sandra Mendoza, Lucy Norcliffe-kaufmann, Susan A SlaugenhauptAbstract:Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients.
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kinetin in familial dysautonomia carriers implications for a new therapeutic strategy targeting mrna splicing
2009Co-Authors: Gabrielle Goldvon Simson, Judith D Goldberg, Linda Rolnitzky, James Mull, Maire Leyne, Andrei Voustianiouk, Susan A Slaugenhaupt, Felicia B AxelrodAbstract:Familial dysautonomia (FD) is caused by an intronic splice mutation in the IκB kinase–associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IκB kinase–associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetin's therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed.
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loss of mouse IKBKAP a subunit of elongator leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP
2009Co-Authors: Yei-tsung Chen, James Mull, Maire Leyne, Matthew M Hims, Lijuan Liu, Ranjit S Shetty, Susan A SlaugenhauptAbstract:Familial dysautonomia (FD), a devastating hereditary sensory and autonomic neuropathy, results from an intronic mutation in the IKBKAP gene that disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP) in the nervous system. To better understand the roles of IKAP in vivo, an IKBKAP knockout mouse model was created. Results from our study show that ablating IKBKAP leads to embryonic lethality, with no homozygous IKBKAP knockout (IKBKAP−/−) embryos surviving beyond 12.5 days postcoitum. Morphological analyses of the IKBKAP−/− conceptus at different stages revealed abnormalities in both the visceral yolk sac and the embryo, including stunted extraembryonic blood vessel formation, delayed entry into midgastrulation, disoriented dorsal primitive neural alignment, and failure to establish the embryonic vascular system. Further, we demonstrate downregulation of several genes that are important for neurulation and vascular development in the IKBKAP−/− embryos and show that this correlates with a defect in transcriptional elongation-coupled histone acetylation. Finally, we show that the embryonic lethality resulting from IKBKAP ablation can be rescued by a human IKBKAP transgene. For the first time, we demonstrate that IKAP is crucial for both vascular and neural development during embryogenesis and that protein function is conserved between mouse and human.
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IKBKAP mrna in peripheral blood leukocytes a molecular marker of gene expression and splicing in familial dysautonomia
2008Co-Authors: Gabrielle Goldvon Simson, Judith D Goldberg, Linda Rolnitzky, James Mull, Maire Leyne, Felicia B Axelrod, Dena Berlin, Susan A SlaugenhauptAbstract:The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IκB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IκB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.
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a humanized IKBKAP transgenic mouse models a tissue specific human splicing defect
2007Co-Authors: Matthew M Hims, James Mull, Maire Leyne, James F Gusella, Lijuan Liu, Ranjit S Shetty, James Pickel, Susan A SlaugenhauptAbstract:Abstract Familial dysautonomia (FD) is a severe hereditary sensory and autonomic neuropathy, and all patients with FD have a splice mutation in the IKBKAP gene. The FD splice mutation results in variable, tissue-specific skipping of exon 20 in IKBKAP mRNA, which leads to reduced IKAP protein levels. The development of therapies for FD will require suitable mouse models for preclinical studies. In this study, we report the generation and characterization of a mouse model carrying the complete human IKBKAP locus with the FD IVS20+6T → C splice mutation. We show that the mutant IKBKAP transgene is misspliced in this model in a tissue-specific manner that replicates the pattern seen in FD patient tissues. Creation of this humanized mouse is the first step toward development of a complex phenotypic model of FD. These transgenic mice are an ideal model system for testing the effectiveness of therapeutic agents that target the missplicing defect. Last, these mice will permit direct studies of tissue-specific splicing and the identification of regulatory factors that play a role in complex gene expression.
James Mull - One of the best experts on this subject based on the ideXlab platform.
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Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
2011Co-Authors: Felicia B Axelrod, Gabrielle Goldvon Simson, James Mull, Maire Leyne, Horacio Kaufmann, Leonard Liebes, Sandra Mendoza, Lucy Norcliffe-kaufmann, Susan A SlaugenhauptAbstract:Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients.
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kinetin in familial dysautonomia carriers implications for a new therapeutic strategy targeting mrna splicing
2009Co-Authors: Gabrielle Goldvon Simson, Judith D Goldberg, Linda Rolnitzky, James Mull, Maire Leyne, Andrei Voustianiouk, Susan A Slaugenhaupt, Felicia B AxelrodAbstract:Familial dysautonomia (FD) is caused by an intronic splice mutation in the IκB kinase–associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IκB kinase–associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetin's therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed.
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loss of mouse IKBKAP a subunit of elongator leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP
2009Co-Authors: Yei-tsung Chen, James Mull, Maire Leyne, Matthew M Hims, Lijuan Liu, Ranjit S Shetty, Susan A SlaugenhauptAbstract:Familial dysautonomia (FD), a devastating hereditary sensory and autonomic neuropathy, results from an intronic mutation in the IKBKAP gene that disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP) in the nervous system. To better understand the roles of IKAP in vivo, an IKBKAP knockout mouse model was created. Results from our study show that ablating IKBKAP leads to embryonic lethality, with no homozygous IKBKAP knockout (IKBKAP−/−) embryos surviving beyond 12.5 days postcoitum. Morphological analyses of the IKBKAP−/− conceptus at different stages revealed abnormalities in both the visceral yolk sac and the embryo, including stunted extraembryonic blood vessel formation, delayed entry into midgastrulation, disoriented dorsal primitive neural alignment, and failure to establish the embryonic vascular system. Further, we demonstrate downregulation of several genes that are important for neurulation and vascular development in the IKBKAP−/− embryos and show that this correlates with a defect in transcriptional elongation-coupled histone acetylation. Finally, we show that the embryonic lethality resulting from IKBKAP ablation can be rescued by a human IKBKAP transgene. For the first time, we demonstrate that IKAP is crucial for both vascular and neural development during embryogenesis and that protein function is conserved between mouse and human.
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IKBKAP mrna in peripheral blood leukocytes a molecular marker of gene expression and splicing in familial dysautonomia
2008Co-Authors: Gabrielle Goldvon Simson, Judith D Goldberg, Linda Rolnitzky, James Mull, Maire Leyne, Felicia B Axelrod, Dena Berlin, Susan A SlaugenhauptAbstract:The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IκB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IκB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.
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Personal correspondance
2008Co-Authors: Yei-tsung Chen, James Mull, Susan A Slaugenhaupt, Matthew M Hims, Lijuan Liu, Ranjit S ShettyAbstract:Loss of mouse IKBKAP, a subunit of Elongator, leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKA
Felicia B Axelrod - One of the best experts on this subject based on the ideXlab platform.
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hereditary sensory autonomic neuropathy caused by a mutation in dystonin
2012Co-Authors: Simon Edvardson, Channa Maayan, Felicia B Axelrod, Yuval Cinnamon, Chaim Jalas, Avraham Shaag, Orly ElpelegAbstract:In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I-κ-B kinase complex-associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders.
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increased incidence of tumors with the IKBKAP gene mutation a case report and review of the literature
2011Co-Authors: Marianna Shvartsbeyn, Felicia B Axelrod, Amy Rapkiewicz, Horacio KaufmannAbstract:An increased incidence of neoplasia was recently reported in patients with familial dysautonomia. This suggests that, in addition to its role in neuronal development, the IKBKAP gene may also influence DNA repair. Here we report the case of a 28-year-old male with familial dysautonomia who was found to have neoplastic lesions detected post mortem as incidental findings. This case indicates that the prevalence of tumorgenesis within this population may be underestimated.
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Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
2011Co-Authors: Felicia B Axelrod, Gabrielle Goldvon Simson, James Mull, Maire Leyne, Horacio Kaufmann, Leonard Liebes, Sandra Mendoza, Lucy Norcliffe-kaufmann, Susan A SlaugenhauptAbstract:Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients.
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olfactory stem cells a new cellular model for studying molecular mechanisms underlying familial dysautonomia
2010Co-Authors: Nathalie Boone, Beatrice Loriod, Aurelie Bergon, Oualid Sbai, Christine Formisanotreziny, Jean Gabert, Michel Khrestchatisky, Catherine Nguyen, Francois Feron, Felicia B AxelrodAbstract:Background Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells.
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Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia. PLoS One
2010Co-Authors: Nathalie Boone, Oualid Sbai, Michel Khrestchatisky, Catherine Nguyen, Felicia B AxelrodAbstract:Background: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells. Methodology/Principal Findings: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/ hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/ hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in F
Berish Y. Rubin - One of the best experts on this subject based on the ideXlab platform.
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IKBKAP elp1 gene mutations mechanisms of familial dysautonomia and gene targeting therapies
2017Co-Authors: Berish Y. Rubin, Sylvia L. AndersonAbstract:The successful completion of the Human Genome Project led to the discovery of the molecular basis of thousands of genetic disorders. The identification of the mutations that cause familial dysautonomia (FD), an autosomal recessive disorder that impacts sensory and autonomic neurons, was aided by the release of the human DNA sequence. The identification and characterization of the genetic cause of FD have changed the natural history of this disease. Genetic testing programs, which were established shortly after the disease-causing mutations were identified, have almost completely eliminated the birth of children with this disorder. Characterization of the principal disease-causing mutation has led to the development of therapeutic modalities that ameliorate its effect, while the development of mouse models that recapitulate the impact of the mutation has allowed for the in-depth characterization of its impact on neuronal development and survival. The intense research focus on this disorder, while clearly benefiting the FD patient population, also serves as a model for the positive impact focused research efforts can have on the future of other genetic diseases. Here, we present the research advances and scientific breakthroughs that have changed and will continue to change the natural history of this centuries-old genetic disease.
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cardiac glycosides correct aberrant splicing of IKBKAP encoded mrna in familial dysautonomia derived cells by suppressing expression of srsf3
2013Co-Authors: Bo Liu, Sylvia L. Anderson, Jinsong Qiu, Berish Y. RubinAbstract:The ability to modulate the production of the wild-type transcript in cells bearing the splice-altering familial dysautonomia (FD) causing mutation in the IKBKAP gene prompted a study of the impact of a panel of pharmaceuticals on the splicing of this transcript, which revealed the ability of the cardiac glycoside digoxin to increase the production of the wild-type, exon-20-containing, IKBKAP-encoded transcript and the full-length IκB-kinase-complex-associated protein in FD-derived cells. Characterization of the cis elements and trans factors involved in the digoxin-mediated effect on splicing reveals that this response is dependent on an SRSF3 binding site(s) located in the intron 5′ of the alternatively spliced exon and that digoxin mediates its effect by suppressing the level of the SRSF3 protein. Characterization of the digoxin-mediated effect on the RNA splicing process was facilitated by the identification of several RNA splicing events in which digoxin treatment mediates the enhanced inclusion of exonic sequence. Moreover, we demonstrate the ability of digoxin to impact the splicing process in neuronal cells, a cell type profoundly impacted by FD. This study represents the first demonstration that digoxin possesses splice-altering capabilities that are capable of reversing the impact of the FD-causing mutation. These findings support the clinical evaluation of the impact of digoxin on the FD patient population.
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nutraceutical mediated restoration of wild type levels of IKBKAP encoded ikap protein in familial dysautonomia derived cells
2012Co-Authors: Sylvia L. Anderson, Jinsong Qiu, Bo Liu, Andrea Sturm, Jamie Schwartz, Austin Peters, Kerry A Sullivan, Berish Y. RubinAbstract:Scope: The reported ability to modulate the production of the wild-type transcript in cells bearing the splice-altering familial dysautonomia (FD)-causing mutation in the IKBKAP gene prompted an evaluation of the impact of commonly consumed nutraceuticals on the splicing of this transcript. Methods and results: Screening efforts revealed the ability of the isoflavones, genistein, and daidzein, to impact splicing and increase the production of the wild-type, exon-20-containing, transcript, and the full-length IKBKAP-encoded IKB kinase complex associated protein (IKAP) in FD-derived cells. Genistein was also found to impact splicing in neuronal cells, a cell type profoundly impacted by FD. The simultaneous exposure of FD-derived cells to genistein and epigallocatechin gallate (EGCG) resulted in the almost exclusive production of the exon-20containing transcript and the production of wild-type amounts of IKAP protein. Conclusion: This study represents the first demonstration that the isoflavones, genistein and daidzein, possess splice-altering capabilities and that simultaneous treatment with genistein and EGCG reverses the splice-altering impact of the FD-causing mutation. These findings support the clinical evaluation of the therapeutic impact of the combined administration of thesetwocommonlyconsumednutraceuticalsonthispatientpopulationandsuggest abroader evaluation of the impact of these nutraceuticals on the in vivo RNA splicing process.
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egcg corrects aberrant splicing of ikap mrna in cells from patients with familial dysautonomia
2003Co-Authors: Sylvia L. Anderson, Jinsong Qiu, Berish Y. RubinAbstract:Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disorder. The most prevalent causative mutation is a T-->C transition in a donor splice site of the IKBKAP transcript, resulting in aberrant splicing and a truncated protein. The mutation's position and leaky nature suggested that its impact might be moderated by altering the level of splice-regulating proteins. The reported ability of (-)-epigallocatechin gallate (EGCG), a polyphenol, to down-regulate the expression of hnRNP A2/B1, a trans-activating factor that encourages the use of intron-distal 5(') splice sites, prompted an evaluation of its effect on the IKBKAP transcript in FD-derived cells. EGCG reduces the level of hnRNP A2/B1 and increases the amounts of the wild-type IKBKAP-encoded transcript and functional protein. Combined treatment of cells with EGCG and tocotrienol, which upregulates IKBKAP transcription, results in a synergistic production of the functional gene product. These findings suggest the possible use of EGCG as a therapeutic modality for individuals with FD.
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tocotrienols induce IKBKAP expression a possible therapy for familial dysautonomia
2003Co-Authors: Sylvia L. Anderson, Jinsong Qiu, Berish Y. RubinAbstract:Familial dysautonomia (FD), a neurodegenerative genetic disorder primarily affecting individuals of Ashkenazi Jewish descent, is caused by mutations in the IKBKAP gene which encodes the IjB kinase complex-associated protein (IKAP). The more common or major mutation causes aberrant splicing, resulting in a truncated form of IKAP. Tissues from individuals homozygous for the major mutation contain both mutant and wild-type IKAP transcripts. The apparent leaky nature of this mutation prompted a search for agents capable of elevating the level of expression of the wild-type IKAP transcript. We report the ability of tocotrienols, members of the vitamin E family, to increase transcription of IKAP mRNA in FD-derived cells, with corresponding increases in the correctly spliced transcript and normal protein. These findings suggest that in vivo supplementation with tocotrienols may elevate IKBKAP gene expression and in turn increase the amount of functional IKAP protein produced in FD patients. 2003Elsevier Science (USA). All rights reserved.
