The Experts below are selected from a list of 1401 Experts worldwide ranked by ideXlab platform
Brent L Fogel - One of the best experts on this subject based on the ideXlab platform.
-
disruption of spermatogenesis and infertility in ataxia with Oculomotor Apraxia type 2 aoa2
The Cerebellum, 2019Co-Authors: Olivier J Becherel, Brent L Fogel, Scott I Zeitlin, Hemamali Samaratunga, Jessica Greaney, Hayden Homer, Martin F LavinAbstract:Ataxia with Oculomotor Apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia characterized by onset between 10 and 20 years of age and a range of neurological features that include progressive cerebellar atrophy, axonal sensorimotor neuropathy, Oculomotor Apraxia in a majority of patients, and elevated serum alpha-fetoprotein (AFP). AOA2 is caused by mutation of the SETX gene which encodes senataxin, a DNA/RNA helicase involved in transcription regulation, RNA processing, and DNA maintenance. Disruption of senataxin in rodents led to defective spermatogenesis and sterility in males uncovering a key role for senataxin in male germ cell survival. Here, we report the first clinical and cellular evidence of impaired spermatogenesis in AOA2 patients. We assessed sperm production in three AOA2 patients and testicular pathology in one patient and compared the findings to those of Setx-knockout mice. Sperm production was impaired in all patients assessed (3/3, 100%). Analyses of testicular biopsies from an AOA2 patient recapitulate features of the histology seen in Setx-knockout mice, strongly suggesting an underlying mechanism centering on DNA-damage-mediated germ cell apoptosis. These findings support a role for senataxin in human reproductive function and highlight a novel clinical feature of AOA2 that extends the extra-neurological roles of senataxin. This raises an important reproductive counseling issue for clinicians, and fertility specialists should be aware of SETX mutations as a possible diagnosis in young male patients presenting with oligospermia or azoospermia since infertility may presage the later onset of neurological manifestations in some individuals.
-
a new model to study neurodegeneration in ataxia Oculomotor Apraxia type 2
Human Molecular Genetics, 2015Co-Authors: Olivier J Becherel, Chiara Criscuolo, Brent L Fogel, Sam P Nayler, Giovanni Coppola, Giuseppe De Michele, Ernst J Wolvetang, Martin F LavinAbstract:Ataxia Oculomotor Apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia. Recent evidence suggests that the protein defective in this syndrome, senataxin (SETX), functions in RNA processing to protect the integrity of the genome. To date, only patient-derived lymphoblastoid cells, fibroblasts and SETX knockdown cells were available to investigate AOA2. Recent disruption of the Setx gene in mice did not lead to neurobehavioral defects or neurodegeneration, making it difficult to study the etiology of AOA2. To develop a more relevant neuronal model to study neurodegeneration in AOA2, we derived neural progenitors from a patient with AOA2 and a control by induced pluripotent stem cell (iPSC) reprogramming of fibroblasts. AOA2 iPSC and neural progenitors exhibit increased levels of oxidative damage, DNA double-strand breaks, increased DNA damage-induced cell death and R-loop accumulation. Genome-wide expression and weighted gene co-expression network analysis in these neural progenitors identified both previously reported and novel affected genes and cellular pathways associated with senataxin dysfunction and the pathophysiology of AOA2, providing further insight into the role of senataxin in regulating gene expression on a genome-wide scale. These data show that iPSCs can be generated from patients with the autosomal recessive ataxia, AOA2, differentiated into neurons, and that both cell types recapitulate the AOA2 cellular phenotype. This represents a novel and appropriate model system to investigate neurodegeneration in this syndrome.
-
mutation of senataxin alters disease specific transcriptional networks in patients with ataxia with Oculomotor Apraxia type 2 p2 126
Neurology, 2015Co-Authors: Brent L Fogel, Chiara Criscuolo, Olivier J Becherel, Alessandro Filla, Giuseppe De Michele, Amanda Wahnich, Xizhe Wang, Francesca Fike, Leslie Chen, Abigail CollinsAbstract:Objective: To assess the functional role of senataxin in cerebellar and motor neuron disease pathogenesis through altered regulation of gene expression. Background: Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with Oculomotor Apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). Design/Methods: Genome-wide transcriptional microarray and RNA-sequencing was used to examine the effect of senataxin mutation on gene expression in cell lines and peripheral blood from AOA2 patients, transfected human cell lines, and Setx knockout mice. Results: We examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. Conclusions: These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4. Disclosure: Dr. Fogel has received personal compensation for activities with the American Physician Institute for Advanced Professional Studies. Dr. Fogel has received personal compensation in an editorial capacity for Neurologic Clinics. Dr. Cho has nothing to disclose. Dr. Wahnich has nothing to disclose. Dr. Gao has nothing to disclose. Dr. Becherel has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Fike has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Criscuolo has nothing to disclose. Dr. De Michele has nothing to disclose. Dr. Filla has nothing to disclose. Dr. Collins has nothing to disclose. Dr. Hahn has nothing to disclose. Dr. Gatti has nothing to disclose. Dr. Konopka has nothing to disclose. Dr. Perlman has received research support from Santhera Pharmaceuticals. Dr. Lavin has nothing to disclose. Dr. Geschwind has received personal compensation for activities with SynapDX, Allen Brain Institute, and Vanderbilt Kennedy Center. Dr. Coppola has nothing to disclose.
-
mutation of senataxin alters disease specific transcriptional networks in patients with ataxia with Oculomotor Apraxia type 2
Human Molecular Genetics, 2014Co-Authors: Brent L Fogel, Chiara Criscuolo, Olivier J Becherel, Alessandro Filla, Giuseppe De Michele, Amanda Wahnich, Xizhe Wang, Francesca Fike, Leslie Chen, Abigail CollinsAbstract:Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with Oculomotor Apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.
-
aberrant splicing of the senataxin gene in a patient with ataxia with Oculomotor Apraxia type 2
The Cerebellum, 2009Co-Authors: Brent L Fogel, Susan PerlmanAbstract:Ataxia with Oculomotor Apraxia type 2 (AOA2) is caused by a diversity of mutations within the coding region of the senataxin gene. Recently, rare noncoding senataxin mutations affecting RNA processing have been identified in AOA2. Here, we report the case of an 18-year-old woman, with classic clinical features of AOA2, who was found to harbor a mutation within senataxin intron 16. This mutation disrupts the local 5′ splice site architecture via a novel intronic frameshift mechanism, causing skipping of exon 16 with predicted disruption of the conserved DNA/RNA helicase domain. RNA processing mutations expand the growing complexity of pathogenic senataxin mutations.
Mariaceu Moreira - One of the best experts on this subject based on the ideXlab platform.
-
Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1
JAMA Neurology, 2018Co-Authors: Mathilde Renaud, Mariaceu Moreira, Bondo Ben Monga, Diana Rodriguez, Rabab Debs, Perrine Charles, Malika Chaouch, Farida Ferrat, Chloe Laurencin, Laurent VercueilAbstract:Importance: Ataxia with Oculomotor Apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, Oculomotor Apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P
-
clinical biomarker and molecular delineations and genotype phenotype correlations of ataxia with Oculomotor Apraxia type 1
JAMA Neurology, 2018Co-Authors: Mariaceu Moreira, Mathilde Renaud, Bondo Ben Monga, Diana Rodriguez, Rabab Debs, Perrine Charles, Malika Chaouch, Farida Ferrat, Chloe LaurencinAbstract:Importance: Ataxia with Oculomotor Apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, Oculomotor Apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor Apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor Apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001). Conclusions and Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor Apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.
-
clinical and molecular findings of ataxia with Oculomotor Apraxia type 2 in 4 families
JAMA Neurology, 2008Co-Authors: Mathieu Anheim, Michel Koenig, Mariaceu Moreira, M Fleury, Jerome Franques, J P Delaunoy, Dominique Stoppalyonnet, C TranchantAbstract:Background Ataxia with Oculomotor Apraxia type 2 (AOA2) is an autosomal recessive disease caused by SETX mutations in 9q34 resulting in cerebellar ataxia in association with peripheral neuropathy, cerebellar atrophy on imaging, an elevated α-fetoprotein (AFP) serum level, and occasional Oculomotor Apraxia. Objective To describe the clinical and molecular findings of 7 patients with a clinical presentation of AOA2 and their relatives. Design Case report. Setting Projet Hospitalier de Recherche Clinique. Patients Seven patients with AOA2 and their family members. Intervention Linkage analysis and direct sequencing of all exons of SETX were performed in all patients. Magnetic resonance imaging and electroneuromyography were performed and the patients' AFP serum levels were tested. Results We identified 7 patients with AOA2 from 4 unrelated families. Three novel SETX mutations were found. The clinical picture of the patients reported is fairly homogeneous and in accordance with the classic AOA2 presentation: onset from 13 to 18 years of progressive cerebellar ataxia and areflexia. Oculomotor Apraxia was detected in 1 patient. Predominant axonal neuropathy and a diffuse cerebellar atrophy were found in the 4 patients tested. All patients had elevated AFP serum levels and 5 of 8 nonsymptomatic heterozygous relatives had moderately increased AFP serum levels as well. Conclusions Ataxia with Oculomotor Apraxia type 2 is a homogeneous form of cerebellar ataxia with occasional Oculomotor Apraxia. Most nonsymptomatic heterozygous carriers present with increased AFP serum levels.
-
chapter 10 recessive ataxia plus Oculomotor Apraxia syndromes
Blue Books of Neurology, 2007Co-Authors: Michel Koenig, Mariaceu MoreiraAbstract:Publisher Summary Ataxia with Oculomotor Apraxia (AOA) is a newly recognized group of recessive ataxias that associate ataxia due to cerebellar atrophy with peripheral sensorimotor neuropathy. Unlike what the name suggests, Oculomotor Apraxia is not an absolute feature of AOA but is a useful diagnostic aid when present. This chapter discusses recessive ataxia plus Oculomotor Apraxia syndromes. Molecular genetic studies have delineated a novel group of recessive ataxias defined by the association of cerebellar atrophy and peripheral sensorimotor neuropathy. This group includes ataxia with Oculomotor Apraxia form 1, defined by late hypoalbuminemia and hypercholesterolemia; ataxia with Oculomotor Apraxia form 2, defined by moderately elevated serum α-fetoprotein (AFP); ataxia-telangiectasia-like disease without elevated serum AFP; and spinocerebellar ataxia with neuropathy (SCAN1), also associated with late hypoalbuminemia. For all four inherited diseases, the gene encodes for a nuclear protein (aprataxin, senataxin, MRE11, and tyrosyl-DNA phosphodiesterase, respectively), which is or may be involved in DNA repair, although the disease causing mutations do not result in cancer predisposition.
-
the ataxia Oculomotor Apraxia 1 gene product has a role distinct from atm and interacts with the dna strand break repair proteins xrcc1 and xrcc4
DNA Repair, 2004Co-Authors: Paula M Clements, Mariaceu Moreira, Philip J Byrd, Malcolm A R Taylor, Claire Breslin, Emma D Deeks, Limei Ju, Pawel Bieganowski, Charles Brenner, Keith W CaldecottAbstract:Ataxia-Oculomotor Apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.
Keith W Caldecott - One of the best experts on this subject based on the ideXlab platform.
-
short patch single strand break repair in ataxia Oculomotor Apraxia 1
Biochemical Society Transactions, 2009Co-Authors: John J Reynolds, Sherif F Elkhamisy, Keith W CaldecottAbstract:AOA1 (ataxia Oculomotor Apraxia-1) results from mutations in aprataxin, a component of DNA strand break repair that removes AMP from 5-termini. In the present article, we provide an overview of this disease and review recent experiments demonstrating that short-patch repair of oxidative single-strand breaks in AOA1 cell extracts bypasses the point of aprataxin action and stalls at the final step of DNA ligation, resulting in accumulation of adenylated DNA nicks. Strikingly, this defect results from insufficient levels of non-adenylated DNA ligase and short-patch single-strand break repair can be restored in AOA1 extracts, independently of aprataxin, by addition of recombinant DNA ligase.
-
defective dna ligation during short patch single strand break repair in ataxia Oculomotor Apraxia 1
Molecular and Cellular Biology, 2009Co-Authors: John J Reynolds, Sherif F Elkhamisy, Sachin Katyal, Paula M Clements, Peter J Mckinnon, Keith W CaldecottAbstract:Ataxia Oculomotor Apraxia 1 (AOA1) results from mutations in aprataxin, a component of DNA strand break repair that removes AMP from 5' termini. Despite this, global rates of chromosomal strand break repair are normal in a variety of AOA1 and other aprataxin-defective cells. Here we show that short-patch single-strand break repair (SSBR) in AOA1 cell extracts bypasses the point of aprataxin action at oxidative breaks and stalls at the final step of DNA ligation, resulting in the accumulation of adenylated DNA nicks. Strikingly, this defect results from insufficient levels of nonadenylated DNA ligase, and short-patch SSBR can be restored in AOA1 extracts, independently of aprataxin, by the addition of recombinant DNA ligase. Since adenylated nicks are substrates for long-patch SSBR, we reasoned that this pathway might in part explain the apparent absence of a chromosomal SSBR defect in aprataxin-defective cells. Indeed, whereas chemical inhibition of long-patch repair did not affect SSBR rates in wild-type mouse neural astrocytes, it uncovered a significant defect in Aptx(-/-) neural astrocytes. These data demonstrate that aprataxin participates in chromosomal SSBR in vivo and suggest that short-patch SSBR arrests in AOA1 because of insufficient nonadenylated DNA ligase.
-
the ataxia Oculomotor Apraxia 1 gene product has a role distinct from atm and interacts with the dna strand break repair proteins xrcc1 and xrcc4
DNA Repair, 2004Co-Authors: Paula M Clements, Mariaceu Moreira, Philip J Byrd, Malcolm A R Taylor, Claire Breslin, Emma D Deeks, Limei Ju, Pawel Bieganowski, Charles Brenner, Keith W CaldecottAbstract:Ataxia-Oculomotor Apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.
-
The ataxia–Oculomotor Apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4
DNA Repair, 2004Co-Authors: Paula M Clements, Mariaceu Moreira, Philip J Byrd, A. Malcolm R. Taylor, Claire Breslin, Emma D Deeks, Limei Ju, Pawel Bieganowski, Charles Brenner, Keith W CaldecottAbstract:Ataxia-Oculomotor Apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.
Martin F Lavin - One of the best experts on this subject based on the ideXlab platform.
-
disruption of spermatogenesis and infertility in ataxia with Oculomotor Apraxia type 2 aoa2
The Cerebellum, 2019Co-Authors: Olivier J Becherel, Brent L Fogel, Scott I Zeitlin, Hemamali Samaratunga, Jessica Greaney, Hayden Homer, Martin F LavinAbstract:Ataxia with Oculomotor Apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia characterized by onset between 10 and 20 years of age and a range of neurological features that include progressive cerebellar atrophy, axonal sensorimotor neuropathy, Oculomotor Apraxia in a majority of patients, and elevated serum alpha-fetoprotein (AFP). AOA2 is caused by mutation of the SETX gene which encodes senataxin, a DNA/RNA helicase involved in transcription regulation, RNA processing, and DNA maintenance. Disruption of senataxin in rodents led to defective spermatogenesis and sterility in males uncovering a key role for senataxin in male germ cell survival. Here, we report the first clinical and cellular evidence of impaired spermatogenesis in AOA2 patients. We assessed sperm production in three AOA2 patients and testicular pathology in one patient and compared the findings to those of Setx-knockout mice. Sperm production was impaired in all patients assessed (3/3, 100%). Analyses of testicular biopsies from an AOA2 patient recapitulate features of the histology seen in Setx-knockout mice, strongly suggesting an underlying mechanism centering on DNA-damage-mediated germ cell apoptosis. These findings support a role for senataxin in human reproductive function and highlight a novel clinical feature of AOA2 that extends the extra-neurological roles of senataxin. This raises an important reproductive counseling issue for clinicians, and fertility specialists should be aware of SETX mutations as a possible diagnosis in young male patients presenting with oligospermia or azoospermia since infertility may presage the later onset of neurological manifestations in some individuals.
-
a new model to study neurodegeneration in ataxia Oculomotor Apraxia type 2
Human Molecular Genetics, 2015Co-Authors: Olivier J Becherel, Chiara Criscuolo, Brent L Fogel, Sam P Nayler, Giovanni Coppola, Giuseppe De Michele, Ernst J Wolvetang, Martin F LavinAbstract:Ataxia Oculomotor Apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia. Recent evidence suggests that the protein defective in this syndrome, senataxin (SETX), functions in RNA processing to protect the integrity of the genome. To date, only patient-derived lymphoblastoid cells, fibroblasts and SETX knockdown cells were available to investigate AOA2. Recent disruption of the Setx gene in mice did not lead to neurobehavioral defects or neurodegeneration, making it difficult to study the etiology of AOA2. To develop a more relevant neuronal model to study neurodegeneration in AOA2, we derived neural progenitors from a patient with AOA2 and a control by induced pluripotent stem cell (iPSC) reprogramming of fibroblasts. AOA2 iPSC and neural progenitors exhibit increased levels of oxidative damage, DNA double-strand breaks, increased DNA damage-induced cell death and R-loop accumulation. Genome-wide expression and weighted gene co-expression network analysis in these neural progenitors identified both previously reported and novel affected genes and cellular pathways associated with senataxin dysfunction and the pathophysiology of AOA2, providing further insight into the role of senataxin in regulating gene expression on a genome-wide scale. These data show that iPSCs can be generated from patients with the autosomal recessive ataxia, AOA2, differentiated into neurons, and that both cell types recapitulate the AOA2 cellular phenotype. This represents a novel and appropriate model system to investigate neurodegeneration in this syndrome.
-
functional role for senataxin defective in ataxia Oculomotor Apraxia type 2 in transcriptional regulation
Human Molecular Genetics, 2009Co-Authors: Amila Suraweera, Rick G Woods, Geoff W Birrell, Talat Nasim, Olivier J Becherel, Martin F LavinAbstract:Ataxia Oculomotor Apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia and Oculomotor Apraxia. The gene mutated in AOA2, SETX, encodes senataxin, a putative DNA/RNA helicase which shares high homology to the yeast Sen1p protein and has been shown to play a role in the response to oxidative stress. To investigate further the function of senataxin, we identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II. Binding of RNA polymerase II to candidate genes was significantly reduced in senataxin deficient cells and this was accompanied by decreased transcription of these genes, suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 and 2. Splicing efficiency of specific mRNAs and alternate splice-site selection of both endogenous genes and artificial minigenes were altered in senataxin depleted cells. These data suggest that senataxin, similar to its yeast homolog Sen1p, plays a role in coordinating transcriptional events, in addition to its role in DNA repair.
-
A subgroup of spinocerebellar ataxias defective in DNA damage responses
Neuroscience, 2007Co-Authors: Nuri Gueven, Olivier J Becherel, Jun Nakamura, Phillip Chen, Amanda W. Kijas, Padraic J. Grattan-smith, Martin F LavinAbstract:A subgroup of human autosomal recessive ataxias is also characterized by disturbances of eye movement or Oculomotor Apraxia. These include ataxia telangiectasia (A-T); ataxia telangiectasia like disorder (ATLD); ataxia Oculomotor Apraxia type 1 (AOA1) and ataxia Oculomotor Apraxia type 2 (AOA2). What appears to be emerging is that all of these have in common some form of defect in DNA damage response which could account for the neurodegenerative changes seen in these disorders. We describe here sensitivity to DNA damaging agents in AOA1 and evidence that these cells have a defect in single strand break repair. Comparison is made with what appears to be a novel form of AOA (AOA3) which also shows sensitivity to agents that lead to single strand breaks in DNA as well as a reduced capacity to repair these breaks. AOA3 cells are defective in the DNA damage-induced p53 response. This defect can be overcome by incubation with the mdm2 antagonists, nutlins, but combined treatment with nutlins and DNA damage does not enhance the response. We also show that AOA3 cells are deficient in p73 activation after DNA damage. These data provide further evidence that different forms of AOA have in common a reduced capacity to cope with damage to DNA, which may account for the neurodegeneration observed in these syndromes.
Olivier J Becherel - One of the best experts on this subject based on the ideXlab platform.
-
disruption of spermatogenesis and infertility in ataxia with Oculomotor Apraxia type 2 aoa2
The Cerebellum, 2019Co-Authors: Olivier J Becherel, Brent L Fogel, Scott I Zeitlin, Hemamali Samaratunga, Jessica Greaney, Hayden Homer, Martin F LavinAbstract:Ataxia with Oculomotor Apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia characterized by onset between 10 and 20 years of age and a range of neurological features that include progressive cerebellar atrophy, axonal sensorimotor neuropathy, Oculomotor Apraxia in a majority of patients, and elevated serum alpha-fetoprotein (AFP). AOA2 is caused by mutation of the SETX gene which encodes senataxin, a DNA/RNA helicase involved in transcription regulation, RNA processing, and DNA maintenance. Disruption of senataxin in rodents led to defective spermatogenesis and sterility in males uncovering a key role for senataxin in male germ cell survival. Here, we report the first clinical and cellular evidence of impaired spermatogenesis in AOA2 patients. We assessed sperm production in three AOA2 patients and testicular pathology in one patient and compared the findings to those of Setx-knockout mice. Sperm production was impaired in all patients assessed (3/3, 100%). Analyses of testicular biopsies from an AOA2 patient recapitulate features of the histology seen in Setx-knockout mice, strongly suggesting an underlying mechanism centering on DNA-damage-mediated germ cell apoptosis. These findings support a role for senataxin in human reproductive function and highlight a novel clinical feature of AOA2 that extends the extra-neurological roles of senataxin. This raises an important reproductive counseling issue for clinicians, and fertility specialists should be aware of SETX mutations as a possible diagnosis in young male patients presenting with oligospermia or azoospermia since infertility may presage the later onset of neurological manifestations in some individuals.
-
a new model to study neurodegeneration in ataxia Oculomotor Apraxia type 2
Human Molecular Genetics, 2015Co-Authors: Olivier J Becherel, Chiara Criscuolo, Brent L Fogel, Sam P Nayler, Giovanni Coppola, Giuseppe De Michele, Ernst J Wolvetang, Martin F LavinAbstract:Ataxia Oculomotor Apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia. Recent evidence suggests that the protein defective in this syndrome, senataxin (SETX), functions in RNA processing to protect the integrity of the genome. To date, only patient-derived lymphoblastoid cells, fibroblasts and SETX knockdown cells were available to investigate AOA2. Recent disruption of the Setx gene in mice did not lead to neurobehavioral defects or neurodegeneration, making it difficult to study the etiology of AOA2. To develop a more relevant neuronal model to study neurodegeneration in AOA2, we derived neural progenitors from a patient with AOA2 and a control by induced pluripotent stem cell (iPSC) reprogramming of fibroblasts. AOA2 iPSC and neural progenitors exhibit increased levels of oxidative damage, DNA double-strand breaks, increased DNA damage-induced cell death and R-loop accumulation. Genome-wide expression and weighted gene co-expression network analysis in these neural progenitors identified both previously reported and novel affected genes and cellular pathways associated with senataxin dysfunction and the pathophysiology of AOA2, providing further insight into the role of senataxin in regulating gene expression on a genome-wide scale. These data show that iPSCs can be generated from patients with the autosomal recessive ataxia, AOA2, differentiated into neurons, and that both cell types recapitulate the AOA2 cellular phenotype. This represents a novel and appropriate model system to investigate neurodegeneration in this syndrome.
-
mutation of senataxin alters disease specific transcriptional networks in patients with ataxia with Oculomotor Apraxia type 2 p2 126
Neurology, 2015Co-Authors: Brent L Fogel, Chiara Criscuolo, Olivier J Becherel, Alessandro Filla, Giuseppe De Michele, Amanda Wahnich, Xizhe Wang, Francesca Fike, Leslie Chen, Abigail CollinsAbstract:Objective: To assess the functional role of senataxin in cerebellar and motor neuron disease pathogenesis through altered regulation of gene expression. Background: Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with Oculomotor Apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). Design/Methods: Genome-wide transcriptional microarray and RNA-sequencing was used to examine the effect of senataxin mutation on gene expression in cell lines and peripheral blood from AOA2 patients, transfected human cell lines, and Setx knockout mice. Results: We examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. Conclusions: These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4. Disclosure: Dr. Fogel has received personal compensation for activities with the American Physician Institute for Advanced Professional Studies. Dr. Fogel has received personal compensation in an editorial capacity for Neurologic Clinics. Dr. Cho has nothing to disclose. Dr. Wahnich has nothing to disclose. Dr. Gao has nothing to disclose. Dr. Becherel has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Fike has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Criscuolo has nothing to disclose. Dr. De Michele has nothing to disclose. Dr. Filla has nothing to disclose. Dr. Collins has nothing to disclose. Dr. Hahn has nothing to disclose. Dr. Gatti has nothing to disclose. Dr. Konopka has nothing to disclose. Dr. Perlman has received research support from Santhera Pharmaceuticals. Dr. Lavin has nothing to disclose. Dr. Geschwind has received personal compensation for activities with SynapDX, Allen Brain Institute, and Vanderbilt Kennedy Center. Dr. Coppola has nothing to disclose.
-
mutation of senataxin alters disease specific transcriptional networks in patients with ataxia with Oculomotor Apraxia type 2
Human Molecular Genetics, 2014Co-Authors: Brent L Fogel, Chiara Criscuolo, Olivier J Becherel, Alessandro Filla, Giuseppe De Michele, Amanda Wahnich, Xizhe Wang, Francesca Fike, Leslie Chen, Abigail CollinsAbstract:Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with Oculomotor Apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.
-
functional role for senataxin defective in ataxia Oculomotor Apraxia type 2 in transcriptional regulation
Human Molecular Genetics, 2009Co-Authors: Amila Suraweera, Rick G Woods, Geoff W Birrell, Talat Nasim, Olivier J Becherel, Martin F LavinAbstract:Ataxia Oculomotor Apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia and Oculomotor Apraxia. The gene mutated in AOA2, SETX, encodes senataxin, a putative DNA/RNA helicase which shares high homology to the yeast Sen1p protein and has been shown to play a role in the response to oxidative stress. To investigate further the function of senataxin, we identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II. Binding of RNA polymerase II to candidate genes was significantly reduced in senataxin deficient cells and this was accompanied by decreased transcription of these genes, suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 and 2. Splicing efficiency of specific mRNAs and alternate splice-site selection of both endogenous genes and artificial minigenes were altered in senataxin depleted cells. These data suggest that senataxin, similar to its yeast homolog Sen1p, plays a role in coordinating transcriptional events, in addition to its role in DNA repair.
