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Akira Sano - One of the best experts on this subject based on the ideXlab platform.
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mouse model of chorea acanthocytosis exhibits male infertility caused by impaired sperm motility as a result of ultrastructural morphological abnormalities in the mitochondrial sheath in the sperm midpiece
Biochemical and Biophysical Research Communications, 2018Co-Authors: Omi Nagata, Masayuki Nakamura, Nari Shiokawa, Natsuki Sasaki, Hitoshi Sakimoto, Yuka Urata, Akira SanoAbstract:Abstract Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis caused by loss-of-function mutations in the Vacuolar Protein Sorting 13 Homolog A (VPS13A) gene, which encodes chorein. We previously produced a ChAc-model mouse with a homozygous deletion of exons 60–61 in VPS13A, which corresponded to the human disease mutation. We found that male ChAc-model mice exhibited complete infertility as a result of severely diminished sperm motility. Immunocytochemical study revealed that chorein-like immunoreactivity is abundant only in the midpiece, mitochondria-rich region, of the sperm of wild type mice. They showed no significant differences from wild types in terms of the adenosine 5′-triphosphate (ATP) concentration of their sperm, sperm count, or sexual activity. Electron microscopy revealed abnormal ultrastructural morphology of the mitochondria in the midpiece of sperm from ChAc-model mice. These results suggest that chorein is essential in mouse sperm for the maintenance of ultrastructural mitochondrial morphology and sperm motility.
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Phenotypic abnormalities in a chorea-acanthocytosis mouse model are modulated by strain background
Biochemical and biophysical research communications, 2016Co-Authors: Hitoshi Sakimoto, Masayuki Nakamura, Omi Nagata, Izumi Yokoyama, Akira SanoAbstract:Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis that is caused by mutations in the VPS13A gene. We previously produced a ChAc model mice encoding a human disease mutation with deletion of exons 60–61 in the VPS13A gene. The behavioral and pathological phenotypes of the model mice varied a good deal from individual to individual, indicating that differences between individuals may be caused by the content of a genetic hybrid 129/Sv and C57BL/6J strain background. To establish the effect of the genetic background on phenotype, we backcrossed the ChAc-model mice to different inbred strains: C57BL/6J and 129S6/Sv. Although no significant difference between ChAc-mutant mice and wild-type mice on the C57BL/6J background was observed, the ChAc-mutant mice on the 129S6/Sv showed abnormal motor function and behavior. Furthermore, we produced ChAc-mutant mice on two different inbred strains: BALB/c and FVB. Significant reduction in weight was observed in ChAc mutant mice on the FVB and 129S6 backgrounds. We found a marked increase in the osmotic fragility of red blood cells in the ChAc mutant mice backcrossed to 129S6/Sv and FVB. The phenotypes varied according to strain, with ChAc mutant mice on the FVB and 129S6 backgrounds showing remarkably abnormal motor function and behavior. These results indicate that there are modifying genetic factors of ChAc symptoms.
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chorein the protein responsible for chorea acanthocytosis interacts with β adducin and β actin
Biochemical and Biophysical Research Communications, 2013Co-Authors: Nari Shiokawa, Masayuki Nakamura, Mieko Sameshima, Akiko Deguchi, Takehiro Hayashi, Natsuki Sasaki, Akira SanoAbstract:Chorea-acanthocytosis (ChAc) is an autosomal, recessive hereditary disease characterized by striatal neurodegeneration and acanthocytosis, and caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene. VPS13A encodes chorein whose physiological function at the molecular level is poorly understood. In this study, we show that chorein interacts with β-adducin and β-actin. We first compare protein expression in human erythrocyte membranes using proteomic analysis. Protein levels of β-adducin isoform 1 and β-actin are markedly decreased in erythrocyte membranes from a ChAc patient. Subsequent co-immunoprecipitation (co-IP) and reverse co-IP assays using extracts from chorein-overexpressing human embryonic kidney 293 (HEK293) cells, shows that β-adducin (isoforms 1 and 2) and β-actin interact with chorein. Immunocytochemical analysis using chorein-overexpressing HEK293 cells demonstrates co-localization of chorein with β-adducin and β-actin. In addition, immunoreactivity of β-adducin isoform 1 is significantly decreased in the striatum of gene-targeted ChAc-model mice. Adducin and actin are membrane cytoskeletal proteins, involved in synaptic function. Expression of β-adducin is restricted to the brain and hematopoietic tissues, corresponding to the main pathological lesions of ChAc, and thereby implicating β-adducin and β-actin in ChAc pathogenesis.
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Comprehensive analysis of the genes responsible for neuroacanthocytosis in mood disorder and schizophrenia
Neuroscience research, 2010Co-Authors: Hirochika Shimo, Shuichi Ueno, Masayuki Nakamura, Mio Ichiba, Akiyuki Tomiyasu, Akira SanoAbstract:Abstract Neuroacanthocytosis syndromes are mainly comprised of two diseases: chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). There is a high incidence of psychiatric disorders such as mood disorder and schizophrenia among neuroacanthocytosis patients. We hypothesized that neuroacanthocytosis-related-genes might be associated with susceptibility to these psychiatric disorders. We performed a comprehensive mutation screen of VPS13A and XK , the gene responsible for ChAc and MLS, respectively, in 85 mood disorder subjects and XK in 86 schizophrenia subjects and compared the variants to 100 or more control alleles. We also performed copy number variation (CNV) analysis in 72 mood disorder subjects and 86 schizophrenia subjects. We identified three non-synonymous, two synonymous and six intron variants in mood disorder subjects and a novel GAT triplet repeat polymorphism in VPS13A . By CNV analysis, we identified a heterozygous exon 60–61 deletion in VPS13A in one mood disorder subject. We identified one non-synonymous and one intron variant in mood disorder and schizophrenia subjects, respectively, in XK . The presence of a pathogenic mutation or a potentially functional variant in mood disorder or schizophrenia subjects suggests that neuroacanthocytosis-related-genes might be involved in the pathogenesis of these psychiatric disorders.
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chorea acanthocytosis with upper motor neuron degeneration and 3419_3420 delca and 3970_3973 delagtc VPS13A mutations
Acta Neuropathologica, 2010Co-Authors: Yasuo Miki, Masayuki Nakamura, Mio Ichiba, Akira Sano, Makoto Nishie, Fumiaki Mori, Masaya Ogawa, Mitsuomi Kaimori, Koichi WakabayashiAbstract:Chorea-acanthocytosis (ChAc) is caused by loss of function mutations of VPS13A gene encoding the large disease protein named chorein [8, 10]. However, McLeod syndrome, Huntington’s disease-like 2, and pantothenate kinase-associated neurodegeneration also present with choreic movements and acanthocytosis. To our knowledge, only five autopsy cases of genetically proven ChAc have been reported [1, 6, 7, 9, 11]. Here, we report an autopsy case of ChAc with upper motor neuron degeneration and with novel VPS13A mutations. A Japanese man developed generalized tonic-clonic seizure at age of 35. At age of 37, he presented with postural instability due to lapse of knees, self-mutilation, orofacial dyskinesia with tongue-biting, involuntary vocalization, and pill-rolling tremor in the left hand. Blood smear showed that 30% of erythrocytes were acanthocytes after 5 min of incubation in normal saline (normal, less than 1%) [5]. Neurological examination showed that deep tendon reflexes in all limbs were absent. Brain CT and MRI revealed mild atrophy of the bilateral caudate nuclei. Genetic analysis revealed no expansion of CAG repeats in the genes of Huntington’s disease and dentatorubral-pallidoluysian atrophy. Expression of Kell antigen of erythrocytes was normal. At age of 42, he was bound to a wheelchair and gradually unable to move his left upper and lower extremities. At age of 47, congestive heart failure became apparent and he died suddenly. Postmortem examination revealed severe degeneration of the neostriatum (Fig. 1a, b). Moderate neuronal loss was found in the substantia nigra pars reticulata and mild in the spinal anterior horn. These findings were consistent with histopathological features of ChAc [12]. Furthermore, neuronal loss in the motor cortex with pyramidal tract degeneration, more severe on the right side, was evident (Fig. 1c–i). No Bunina bodies or TDP-43-positive inclusions were noted in the upper and lower motor neurons. Genetic analysis revealed two novel heterozygous mutations in exon 32 (c.3419_3420 delCA) and exon 35 (c.3970_3973 delAGTC) of the VPS13A gene (Fig. 2). Both mutations, which lead to premature stop codon further downstream resulting in truncated chorein, are considered to be pathogenic. Although epilepsy has been well recognized in patients with ChAc [2], the cortical degeneration in our case is not due to epilepsy, because of the absence of neuronal loss or gliosis in the medial temporal lobe. Moreover, no Bunina bodies or TDP-43-immunoreactive inclusions were noted in our case. Therefore, complication of neurodegenerative diseases causing bilateral pyramidal tract degeneration, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration with motor neuron disease, appeared to be excluded. Although the inheritance of ChAc is widely known as autosomal recessive, single heterozygous VPS13A Y. Miki (&) F. Mori K. Wakabayashi Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan e-mail: yasuomiki@hotmail.com
Elizabeth Conibear - One of the best experts on this subject based on the ideXlab platform.
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The Vps13 Family of Lipid Transporters and Its Role at Membrane Contact Sites.
International journal of molecular sciences, 2021Co-Authors: Samantha Katarzyna Dziurdzik, Elizabeth ConibearAbstract:The conserved VPS13 proteins constitute a new family of lipid transporters at membrane contact sites. These large proteins are suspected to bridge membranes and form a direct channel for lipid transport between organelles. Mutations in the 4 human homologs (VPS13A-D) are associated with a number of neurological disorders, but little is known about their precise functions or the relevant contact sites affected in disease. In contrast, yeast has a single Vps13 protein which is recruited to multiple organelles and contact sites. The yeast model system has proved useful for studying the function of Vps13 at different organelles and identifying the localization determinants responsible for its membrane targeting. In this review we describe recent advances in our understanding of VPS13 proteins with a focus on yeast research.
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A VPS13D spastic ataxia mutation disrupts the conserved adaptor-binding site in yeast Vps13.
Human molecular genetics, 2020Co-Authors: Samantha K. Dziurdzik, Björn D. M. Bean, Michael Davey, Elizabeth ConibearAbstract:Mutations in each of the four human VPS13 (VPS13A-D) proteins are associated with distinct neurological disorders: chorea-acanthocytosis, Cohen syndrome, early-onset Parkinson's disease and spastic ataxia. Recent evidence suggests that the different VPS13 paralogs transport lipids between organelles at different membrane contact sites. How each VPS13 isoform is targeted to organelles is not known. We have shown that the localization of yeast Vps13 protein to membranes requires a conserved six-repeat region, the Vps13 Adaptor Binding (VAB) domain, which binds to organelle-specific adaptors. Here, we use a systematic mutagenesis strategy to determine the role of each repeat in recognizing each known adaptor. Our results show that mutation of invariant asparagines in repeats 1 and 6 strongly impacts the binding of all adaptors and blocks Vps13 membrane recruitment. However, we find that repeats 5-6 are sufficient for localization and interaction with adaptors. This supports a model where a single adaptor-binding site is found in the last two repeats of the VAB domain, while VAB domain repeat 1 may influence domain conformation. Importantly, a disease-causing mutation in VPS13D, which maps to the highly conserved asparagine residue in repeat 6, blocks adaptor binding and Vps13 membrane recruitment when modeled in yeast. Our findings are consistent with a conserved adaptor binding role for the VAB domain and suggest the presence of as-yet-unidentified adaptors in both yeast and humans.
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A VPS13D spastic ataxia mutation disrupts the conserved adaptor binding site in yeast Vps13
2019Co-Authors: Samantha K. Dziurdzik, Björn D. M. Bean, Michael Davey, Elizabeth ConibearAbstract:Abstract Mutations in each of the four human VPS13 (VPS13A-D) proteins are associated with distinct neurological disorders: chorea-acanthocytosis, Cohen syndrome, early-onset Parkinson’s disease and spastic ataxia. Recent evidence suggests that the different VPS13 paralogs transport lipids between organelles at different membrane contact sites. How each VPS13 isoform is targeted to organelles is not known. We have shown that the localization of yeast Vps13 protein to membranes requires a conserved six-repeat region, the Vps13 Adaptor Binding (VAB) domain, which binds to organelle-specific adaptors. Here, we use a systematic mutagenesis strategy to determine the role of each repeat in recognizing each known adaptor. Our results show that mutation of invariant asparagines in repeats 1 and 6 strongly impact the binding all adaptors and block Vps13 membrane recruitment. However, we find that repeats 5 to 6 are sufficient for localization and interaction with adaptors. This supports a model where a single adaptor binding site is found in the last two repeats of the VAB domain, while VAB domain repeat 1 may help maintain domain conformation. Importantly, a disease-causing mutation in VPS13D, which maps to the highly conserved asparagine residue in repeat 6, blocks adaptor binding and Vps13 membrane recruitment when modeled in yeast. Our findings are consistent with a conserved adaptor binding role for the VAB domain and suggests the presence of as-yet-unidentified adaptors in both yeast and humans.
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Competitive organelle-specific adaptors recruit Vps13 to membrane contact sites.
The Journal of cell biology, 2018Co-Authors: Björn D. M. Bean, Samantha K. Dziurdzik, Michael Davey, Kathleen L. Kolehmainen, Claire M.s. Fowler, Waldan K. Kwong, Leslie I. Grad, Cayetana Schluter, Elizabeth ConibearAbstract:The regulated expansion of membrane contact sites, which mediate the nonvesicular exchange of lipids between organelles, requires the recruitment of additional contact site proteins. Yeast Vps13 dynamically localizes to membrane contacts that connect the ER, mitochondria, endosomes, and vacuoles and is recruited to the prospore membrane in meiosis, but its targeting mechanism is unclear. In this study, we identify the sorting nexin Ypt35 as a novel adaptor that recruits Vps13 to endosomal and vacuolar membranes. We characterize an interaction motif in the Ypt35 N terminus and identify related motifs in the prospore membrane adaptor Spo71 and the mitochondrial membrane protein Mcp1. We find that Mcp1 is a mitochondrial adaptor for Vps13, and the Vps13-Mcp1 interaction, but not Ypt35, is required when ER-mitochondria contacts are lost. All three adaptors compete for binding to a conserved six-repeat region of Vps13 implicated in human disease. Our results support a competition-based model for regulating Vps13 localization at cellular membranes.
Masayuki Nakamura - One of the best experts on this subject based on the ideXlab platform.
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novel pathogenic VPS13A gene mutations in japanese patients with chorea acanthocytosis
Neurology Genetics, 2019Co-Authors: Yoshiaki Nishida, Masayuki Nakamura, Yuka Urata, Kei Kasamo, Hanae Hiwatashi, Izumi Yokoyama, Masahiro Mizobuchi, Kotaro Sakurai, Yasushi Osaki, Yukari MoritaAbstract:Objective To identify mutations in vacuolar protein sorting 13A ( VPS13A ) for Japanese patients with suspected chorea-acanthocytosis (ChAc). Methods We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. Results We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60–61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. Conclusions We identified 13 different mutations in VPS13A , including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.
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mouse model of chorea acanthocytosis exhibits male infertility caused by impaired sperm motility as a result of ultrastructural morphological abnormalities in the mitochondrial sheath in the sperm midpiece
Biochemical and Biophysical Research Communications, 2018Co-Authors: Omi Nagata, Masayuki Nakamura, Nari Shiokawa, Natsuki Sasaki, Hitoshi Sakimoto, Yuka Urata, Akira SanoAbstract:Abstract Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis caused by loss-of-function mutations in the Vacuolar Protein Sorting 13 Homolog A (VPS13A) gene, which encodes chorein. We previously produced a ChAc-model mouse with a homozygous deletion of exons 60–61 in VPS13A, which corresponded to the human disease mutation. We found that male ChAc-model mice exhibited complete infertility as a result of severely diminished sperm motility. Immunocytochemical study revealed that chorein-like immunoreactivity is abundant only in the midpiece, mitochondria-rich region, of the sperm of wild type mice. They showed no significant differences from wild types in terms of the adenosine 5′-triphosphate (ATP) concentration of their sperm, sperm count, or sexual activity. Electron microscopy revealed abnormal ultrastructural morphology of the mitochondria in the midpiece of sperm from ChAc-model mice. These results suggest that chorein is essential in mouse sperm for the maintenance of ultrastructural mitochondrial morphology and sperm motility.
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Phenotypic abnormalities in a chorea-acanthocytosis mouse model are modulated by strain background
Biochemical and biophysical research communications, 2016Co-Authors: Hitoshi Sakimoto, Masayuki Nakamura, Omi Nagata, Izumi Yokoyama, Akira SanoAbstract:Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis that is caused by mutations in the VPS13A gene. We previously produced a ChAc model mice encoding a human disease mutation with deletion of exons 60–61 in the VPS13A gene. The behavioral and pathological phenotypes of the model mice varied a good deal from individual to individual, indicating that differences between individuals may be caused by the content of a genetic hybrid 129/Sv and C57BL/6J strain background. To establish the effect of the genetic background on phenotype, we backcrossed the ChAc-model mice to different inbred strains: C57BL/6J and 129S6/Sv. Although no significant difference between ChAc-mutant mice and wild-type mice on the C57BL/6J background was observed, the ChAc-mutant mice on the 129S6/Sv showed abnormal motor function and behavior. Furthermore, we produced ChAc-mutant mice on two different inbred strains: BALB/c and FVB. Significant reduction in weight was observed in ChAc mutant mice on the FVB and 129S6 backgrounds. We found a marked increase in the osmotic fragility of red blood cells in the ChAc mutant mice backcrossed to 129S6/Sv and FVB. The phenotypes varied according to strain, with ChAc mutant mice on the FVB and 129S6 backgrounds showing remarkably abnormal motor function and behavior. These results indicate that there are modifying genetic factors of ChAc symptoms.
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chorein the protein responsible for chorea acanthocytosis interacts with β adducin and β actin
Biochemical and Biophysical Research Communications, 2013Co-Authors: Nari Shiokawa, Masayuki Nakamura, Mieko Sameshima, Akiko Deguchi, Takehiro Hayashi, Natsuki Sasaki, Akira SanoAbstract:Chorea-acanthocytosis (ChAc) is an autosomal, recessive hereditary disease characterized by striatal neurodegeneration and acanthocytosis, and caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene. VPS13A encodes chorein whose physiological function at the molecular level is poorly understood. In this study, we show that chorein interacts with β-adducin and β-actin. We first compare protein expression in human erythrocyte membranes using proteomic analysis. Protein levels of β-adducin isoform 1 and β-actin are markedly decreased in erythrocyte membranes from a ChAc patient. Subsequent co-immunoprecipitation (co-IP) and reverse co-IP assays using extracts from chorein-overexpressing human embryonic kidney 293 (HEK293) cells, shows that β-adducin (isoforms 1 and 2) and β-actin interact with chorein. Immunocytochemical analysis using chorein-overexpressing HEK293 cells demonstrates co-localization of chorein with β-adducin and β-actin. In addition, immunoreactivity of β-adducin isoform 1 is significantly decreased in the striatum of gene-targeted ChAc-model mice. Adducin and actin are membrane cytoskeletal proteins, involved in synaptic function. Expression of β-adducin is restricted to the brain and hematopoietic tissues, corresponding to the main pathological lesions of ChAc, and thereby implicating β-adducin and β-actin in ChAc pathogenesis.
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novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea acanthocytosis
American Journal of Medical Genetics, 2011Co-Authors: Akiyuki Tomiyasu, Shuichi Ueno, Masayuki Nakamura, Yasufumi Kageyama, Jan Kobal, Shinji Saiki, Mio Ichiba, Mizuki Morimoto, Toshio Inui, Koichi WakabayashiAbstract:Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.
Aaron M Neiman - One of the best experts on this subject based on the ideXlab platform.
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xk is a partner for VPS13A a molecular link between chorea acanthocytosis and mcleod syndrome
Molecular Biology of the Cell, 2020Co-Authors: Jaesook Park, Aaron M NeimanAbstract:Vps13 is a highly conserved lipid transfer protein found at multiple interorganelle membrane contact sites where it mediates distinct processes. In yeast, recruitment of Vps13 to different contact sites occurs via various partner proteins. In humans, four VPS13 family members, A-D, are associated with different diseases. In particular, VPS13A mutants result in the neurodegenerative disorder Chorea-Acanthocytosis (ChAc). ChAc phenotypes resemble those of McLeod Syndrome, caused by mutations in the XK gene, suggesting that XK could be a partner protein for VPS13A. XK does, in fact, exhibit hallmarks of a VPS13A partner: it forms a complex with VPS13A in human cells and, when overexpressed, relocalizes VPS13A from lipid droplets to subdomains of the endoplasmic reticulum. Introduction of two different ChAc disease-linked missense mutations into VPS13A prevents this XK-induced relocalization. These results suggest that dysregulation of a VPS13A-XK complex is the common basis for ChAc and McLeod Syndrome.
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Yeast Vps13 promotes mitochondrial function and is localized at membrane contact sites
Molecular biology of the cell, 2016Co-Authors: Jaesook Park, Mary K. Thorsness, Robert A. Policastro, Luke L. Mcgoldrick, Nancy M. Hollingsworth, Peter E. Thorsness, Aaron M NeimanAbstract:The Vps13 protein family is highly conserved in eukaryotic cells. Mutations in human VPS13 genes result in a variety of diseases, such as chorea acanthocytosis (ChAc), but the cellular functions of Vps13 proteins are not well defined. In yeast, there is a single VPS13 orthologue, which is required for at least two different processes: protein sorting to the vacuole and sporulation. This study demonstrates that VPS13 is also important for mitochondrial integrity. In addition to preventing transfer of DNA from the mitochondrion to the nucleus, VPS13 suppresses mitophagy and functions in parallel with the endoplasmic reticulum-mitochondrion encounter structure (ERMES). In different growth conditions, Vps13 localizes to endosome-mitochondrion contacts and to the nuclear-vacuole junctions, indicating that Vps13 may function at membrane contact sites. The ability of VPS13 to compensate for the absence of ERMES correlates with its intracellular distribution. We propose that Vps13 is present at multiple membrane contact sites and that separation-of-function mutants are due to loss of Vps13 at specific junctions. Introduction of VPS13A mutations identified in ChAc patients at cognate sites in yeast VPS13 are specifically defective in compensating for the lack of ERMES, suggesting that mitochondrial dysfunction might be the basis for ChAc.
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A Conserved Function in Phosphatidylinositol Metabolism for Mammalian Vps13 Family Proteins
PloS one, 2015Co-Authors: Jaesook Park, Simon Halegoua, Shosei Kishida, Aaron M NeimanAbstract:The Vps13 protein family is highly conserved in eukaryotic cells. In humans, mutations in the gene encoding the family member VPS13A lead to the neurodegenerative disorder chorea-acanthocytosis. In the yeast Saccharomyces cerevisiae, there is just a single version of VPS13, thereby simplifying the task of unraveling its molecular function(s). While VPS13 was originally identified in yeast by its role in vacuolar sorting, recent studies have revealed a completely different function for VPS13 in sporulation, where VPS13 regulates phosphatidylinositol-4-phosphate (PtdIns(4)P) levels in the prospore membrane. This discovery raises the possibility that the disease phenotype associated with VPS13A mutants in humans is due to misregulation of PtdIns(4)P in membranes. To determine whether VPS13A affects PtdIns(4)P in membranes from mammalian neuronal cells, phosphatidylinositol phosphate pools were compared in PC12 tissue culture cells in the absence or presence of VPS13A. Consistent with the yeast results, the localization of PtdIns(4)P is specifically altered in VPS13A knockdown cells while other phosphatidylinositol phosphates appear unaffected. In addition, VPS13A is necessary to prevent the premature degeneration of neurites that develop in response to Nerve Growth Factor. The regulation of PtdIns(4)P is therefore a conserved function of the Vps13 family and may play a role in the maintenance of neuronal processes in mammals.
Adrian Danek - One of the best experts on this subject based on the ideXlab platform.
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Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis
Molecular genetics & genomic medicine, 2020Co-Authors: Derek Spieler, Benedikt Bader, Antonio Velayos-baeza, Alžbeta Muhlback, Florian Castrop, Christian Maegerlein, Bernhard Haslinger, Julia Slotta-huspenina, Adrian DanekAbstract:Background Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. Methods Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. Results We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. Conclusion Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.
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identification of two compound heterozygous VPS13A large deletions in chorea acanthocytosis only by protein and quantitative dna analysis
Molecular Genetics & Genomic Medicine, 2020Co-Authors: Benedikt Bader, Antonio Velayosbaeza, Derek Spieler, Alžbeta Muhlback, Florian Castrop, Christian Maegerlein, Julia Slottahuspenina, Bernhard Haslinger, Adrian DanekAbstract:Background Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. Methods Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. Results We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. Conclusion Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.
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Frühdiagnose der Chorea-Akanthozytose: orofaziale Dyskinesien, epileptische Anfälle und HyperCKämie
Fortschritte Der Neurologie Psychiatrie, 2017Co-Authors: Christian A. Schneider, Adrian Danek, Arwed Hostmann, Gereon R Fink, Lothar BurghausAbstract:Chorea-acanthocytosis is an uncommon neurodegenerative disorder. Early diagnosis is often challenging. The triad of orofacial dyskinesia, epileptic seizures, and hyperCKemia should alert neurologists of a neuroacanthocytosis syndrome. The diagnosis can be confirmed by detection of chorein deficiency or through molecular genetics (VPS13A mutation).
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Early Diagnosis of Chorea-Acanthocytosis: Orofacial Dyskinesia, Epileptic Seizures, and HyperCKemia
Fortschritte der Neurologie-Psychiatrie, 2017Co-Authors: Christian Schneider, Adrian Danek, Arwed Hostmann, Gereon R Fink, Lothar BurghausAbstract:Chorea-acanthocytosis is an uncommon neurodegenerative disorder. Early diagnosis is often challenging. The triad of orofacial dyskinesia, epileptic seizures, and hyperCKemia should alert neurologists of a neuroacanthocytosis syndrome. The diagnosis can be confirmed by detection of chorein deficiency or through molecular genetics (VPS13A mutation).
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identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. PLoS One 2012
2016Co-Authors: Lucia De Franceschi, Benedikt Bader, Adrian Danek, Ruth H. Walker, Maria Teresa Dotti, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Sara Mazzucco, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks b
