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Andrew H. Crosby - One of the best experts on this subject based on the ideXlab platform.
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Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel
BMC Medical Genetics, 2016Co-Authors: Sharon Aharoni, Katy E. S. Barwick, Rachel Straussberg, Gaurav V. Harlalka, Yoram Nevo, Barry A. Chioza, Meriel M. Mcentagart, Aviva Mimouni-bloch, Michael Weedon, Andrew H. CrosbyAbstract:Background CMT-2 is a clinically and genetically heterogeneous group of peripheral Axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical Giant Axonal Neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of “kinky” hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN , encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation. Methods An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair. Results Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement. Conclusions Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone.
Pascale Bomont - One of the best experts on this subject based on the ideXlab platform.
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Giant Axonal Neuropathy associated gigaxonin mutations impair intermediate filament protein degradation
Journal of Clinical Investigation, 2013Co-Authors: Saleemulla Mahammad, Pascale Bomont, S Prasanna N Murthy, Alessandro Didonna, Boris Grin, Eitan Israeli, Rodolphe Perrot, Jeanpierre Julien, Edward R Kuczmarski, Puneet OpalAbstract:Giant Axonal Neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.
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Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway
Human molecular genetics, 2009Co-Authors: Don W. Cleveland, Koji Yamanaka, Pascale BomontAbstract:Gigaxonin mutations cause the fatal human neurodegenerative disorder Giant Axonal Neuropathy (GAN). Broad deterioration of the nervous system in GAN patients is accompanied by massive disorganization of intermediate filaments (IFs) both in neurons and many non-neuronal cells. With newly developed antibodies, gigaxonin is now shown to be expressed at extremely low levels throughout the nervous system. In lymphoblast cell lines derived from severe and mild forms of GAN, mutations in gigaxonin are shown to yield highly unstable proteins, thereby permitting a rapid diagnostic test for the spectrum of GAN mutations as an alternative to invasive nerve biopsy or systematic sequencing of the GAN gene. Gigaxonin has been proposed as a substrate adaptor for an E3 ubiquitin ligase, which affects proteasome-dependent degradation of microtubule-related proteins including MAP1B, MAP8 and the tubulin folding chaperone TBCB. We demonstrate that, unlike its counterpart TBCE, TBCB only moderately destabilizes microtubules. Neither TBCB abundance nor microtubule organization or densities are altered in GAN mutant fibroblasts, thus demonstrating that altered TBCB levels are not primary determinants of IF disorganization in GAN. Characteristic GAN mutant-induced ovoid aggregates of vimentin are not produced in normal fibroblasts after disrupting microtubule assembly, either by TBCE overexpression or depolymerizing drugs. Thus, IF disorganization in GAN fibroblasts is independent of TBCB and microtubule loss and must be regulated by a yet unidentified mechanism.
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Giant Axonal Neuropathy: clinical and genetic study in six cases.
Journal of Neurology Neurosurgery and Psychiatry, 2005Co-Authors: E. Demir, Pascale Bomont, Laurent Cavalier, S. Erdem, M. Demirci, G. Kose, S. Muftuoglu, A. N. Cakar, E. Tan, S. AysunAbstract:BACKGROUND: Giant Axonal Neuropathy (GAN) is a severe recessive disorder characterised by variable combination of progressive sensory motor Neuropathy, central nervous system (CNS) involvement, and "frizzly" hair. The disease is caused by GAN gene mutations on chromosome 16q24.1. AIMS: To search for GAN gene mutations in Turkish patients with GAN and characterise the phenotype associated with them. METHODS: Linkage and mutation analyses were performed in six affected patients from three consanguineous families. These patients were also investigated by cranial magnetic resonance imaging (MRI) and electroencephalography (EEG). Electromyography (EMG) was performed in heterozygous carriers from family 1 and family 3. RESULTS: Linkage to 16q24.1 was confirmed by haplotype analysis. GAN mutations were identified in all families. Family 1 had the R293X mutation, previously reported in another Turkish family. Families 2 and 3, originating from close geographical areas, shared a novel mutation, 1502+1G>T, at the donor splice site of exon 9. All patients displayed a common phenotype, including peripheral Neuropathy, cerebellar ataxia, and frizzly hair. Cranial MRI showed diffuse white matter abnormalities in two patients from family 1 and the patient from family 3, and minimal white matter involvement in the patient from family 2. EMG of a heterozygous R293X mutation carrier showed signs of mild Axonal Neuropathy, whereas a 1502+1G>T mutation carrier had normal EMG. EEG abnormalities were found in three patients. CONCLUSION: These findings highlight the association of CNS involvement, in particular white matter abnormalities, with peripheral Neuropathy in GAN. The phenotypical consequences of both mutations (when homozygous) were similar.
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the gene encoding gigaxonin a new member of the cytoskeletal btb kelch repeat family is mutated in Giant Axonal Neuropathy
Nature Genetics, 2000Co-Authors: Pascale Bomont, Laurent Cavalier, François Blondeau, Christiane Ben Hamida, Samir Belal, Meriem Tazir, Ercan Demir, Haluk Topaloglu, Rudolf Korinthenberg, Beyhan TüysüzAbstract:Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and Axonal Charcot-Marie-Tooth disease. Giant Axonal Neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor Neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.
Sharon Aharoni - One of the best experts on this subject based on the ideXlab platform.
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Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel
BMC Medical Genetics, 2016Co-Authors: Sharon Aharoni, Katy E. S. Barwick, Rachel Straussberg, Gaurav V. Harlalka, Yoram Nevo, Barry A. Chioza, Meriel M. Mcentagart, Aviva Mimouni-bloch, Michael Weedon, Andrew H. CrosbyAbstract:Background CMT-2 is a clinically and genetically heterogeneous group of peripheral Axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical Giant Axonal Neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of “kinky” hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN , encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation. Methods An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair. Results Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement. Conclusions Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone.
Yanmin Yang - One of the best experts on this subject based on the ideXlab platform.
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gigaxonin interacts with tubulin folding cofactor b and controls its degradation through the ubiquitin proteasome pathway
Current Biology, 2005Co-Authors: Wei Wang, Jianqing Ding, Elizabeth Allen, Hannes Vogel, Ping Zhu, Lan Zhang, Yanmin YangAbstract:Gigaxonin is mutated in human Giant Axonal Neuropathy (GAN), an autosomal recessive neurodegenerative disorder. The presence of generalized cytoskeletal abnormalities , including few microtubules and accumulated intermediate filaments (IFs), in GAN suggests an essential role of gigaxonin in cytoskeletal organization and dynamics. However, the molecular mechanisms underlying the cytoskeletal pathology remain to be elucidated. Over the years, the ubiquitin-proteasome system (UPS) of intracellular protein degradation has been implicated in the control of many fundamental cellular processes. Defects in this system seem to be directly linked to the development of human diseases, including cancers and neurodegenerative diseases . Here, we show that gigaxonin controls protein degradation of tubulin folding cofactor B (TBCB) , a function disrupted by GAN-associated mutations. The substantial TBCB protein accumulation caused by impaired UPS may be a causative factor of cytoskeletal pathology in GAN. Our study provides important insight into pathogenesis of neurodegenerative diseases associated with cytoskeletal abnormalities.
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gigaxonin controlled degradation of map1b light chain is critical to neuronal survival
Nature, 2005Co-Authors: Elizabeth Allen, Jianqing Ding, Wei Wang, Suneet Pramanik, Jonathan Chou, Yanmin YangAbstract:Giant Axonal Neuropathy (GAN) is a rare and debilitating inherited condition that generally appears in early childhood. It is caused by mutations in the GAN gene that encodes gigaxonin, a member of the BTB/kelch superfamily of cytoskeletal proteins. Gigaxonin has now been identified as a ubiquitin-scaffolding protein that is essential for neuronal function and survival through its control of the degradation of the light chain of microtubule-associated protein 1B. This is of particular interest since alterations in the cytoskeletal network are also a feature of more common diseases such as amyotrophic lateral sclerosis, so knowledge of the function of gigaxonin may provide insights into the pathogenesis of neurodegenerative disorders in general. Giant Axonal Neuropathy (GAN) is a devastating sensory and motor Neuropathy caused by mutations in the GAN gene, which encodes the ubiquitously expressed protein gigaxonin1,2,3,4,5. Cytopathological features of GAN include Axonal degeneration, with accumulation and aggregation of cytoskeletal components6,7. Little is currently known about the molecular mechanisms underlying this recessive disorder. Here we show that gigaxonin controls protein degradation, and is essential for neuronal function and survival. We present evidence that gigaxonin binds to the ubiquitin-activating enzyme E1 through its amino-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of microtubule-associated protein 1B (MAP1B)8. Overexpression of gigaxonin leads to enhanced degradation of MAP1B-LC, which can be antagonized by proteasome inhibitors. Ablation of gigaxonin causes a substantial accumulation of MAP1B-LC in GAN-null neurons. Moreover, we show that overexpression of MAP1B in wild-type cortical neurons leads to cell death characteristic of GAN-null neurons, whereas reducing MAP1B levels significantly improves the survival rate of null neurons. Our results identify gigaxonin as a ubiquitin scaffolding protein that controls MAP1B-LC degradation, and provide insight into the molecular mechanisms underlying human neurodegenerative disorders.
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Microtubule-associated protein 1B: a neuronal binding partner for gigaxonin
2002Co-Authors: Jianqing Ding, Timothy Nardine, Jia-jia Liu, Anthony S. Kowal, Priyanka Bhattacharya, Arthur Lee, Yanmin YangAbstract:Giant Axonal Neuropathy (GAN), an autosomal recessive disorder caused by mutations in GAN, is characterized cytopathologically by cytoskeletal abnormality. Based on its sequence, gigaxonin contains an NH2-terminal BTB domain followed by six kelch repeats, which are believed to be important for protein–protein interactions (Adams, J., R. Kelso, and L. Cooley. 2000. Trends Cell Biol. 10:17–24.). Here, we report the identification of a neuronal binding partner of gigaxonin. Results obtained from yeast two-hybrid screening, cotransfections, and coimmunoprecipitations demonstrate that gigaxonin binds directly to microtubule-associated protein (MAP)1B light chain (LC; MAP1B-LC), a protein involved in maintaining the integrity of cytoskeletal structures and promoting neuronal stability. Studies using double immunofluorescent microscopy and ultrastructural analysis revealed physiological colocalization of gigaxonin with MAP1B in neurons. Furthermore, in transfected cells the specific interaction of gigaxonin with MAP1B is shown to enhance the microtubule stability required for Axonal transport over long distance. At least two different mutations identified in GAN patient
Elizabeth Allen - One of the best experts on this subject based on the ideXlab platform.
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gene targeting of gan in mouse causes a toxic accumulation of microtubule associated protein 8 and impaired retrograde Axonal transport
Human Molecular Genetics, 2006Co-Authors: Jianqing Ding, Elizabeth Allen, Wei Wang, Angela Valle, Timothy Nardine, Bianxiao Cui, Anne Marion Taylor, Noo Li Jeon, Steven Chu, Hannes VogelAbstract:Mutations in gigaxonin were identified in Giant Axonal Neuropathy (GAN), an autosomal recessive disorder. To understand how disruption of gigaxonin's function leads to neurodegeneration, we ablated the gene expression in mice using traditional gene targeting approach. Progressive neurological phenotypes and pathological lesions that developed in the GAN null mice recapitulate characteristic human GAN features. The disruption of gigaxonin results in an impaired ubiquitin-proteasome system leading to a substantial accumulation of a novel microtubule-associated protein, MAP8, in the null mutants. Accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures and leads to neuronal death in cultured wild-type neurons, which replicates the process occurring in GAN null mutants. Defective Axonal transport is evidenced by the in vitro assays and is supported by vesicular accumulation in the GAN null neurons. We propose that the Axonal transport impairment may be a deleterious consequence of accumulated, toxic MAP8 protein.
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gigaxonin interacts with tubulin folding cofactor b and controls its degradation through the ubiquitin proteasome pathway
Current Biology, 2005Co-Authors: Wei Wang, Jianqing Ding, Elizabeth Allen, Hannes Vogel, Ping Zhu, Lan Zhang, Yanmin YangAbstract:Gigaxonin is mutated in human Giant Axonal Neuropathy (GAN), an autosomal recessive neurodegenerative disorder. The presence of generalized cytoskeletal abnormalities , including few microtubules and accumulated intermediate filaments (IFs), in GAN suggests an essential role of gigaxonin in cytoskeletal organization and dynamics. However, the molecular mechanisms underlying the cytoskeletal pathology remain to be elucidated. Over the years, the ubiquitin-proteasome system (UPS) of intracellular protein degradation has been implicated in the control of many fundamental cellular processes. Defects in this system seem to be directly linked to the development of human diseases, including cancers and neurodegenerative diseases . Here, we show that gigaxonin controls protein degradation of tubulin folding cofactor B (TBCB) , a function disrupted by GAN-associated mutations. The substantial TBCB protein accumulation caused by impaired UPS may be a causative factor of cytoskeletal pathology in GAN. Our study provides important insight into pathogenesis of neurodegenerative diseases associated with cytoskeletal abnormalities.
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gigaxonin controlled degradation of map1b light chain is critical to neuronal survival
Nature, 2005Co-Authors: Elizabeth Allen, Jianqing Ding, Wei Wang, Suneet Pramanik, Jonathan Chou, Yanmin YangAbstract:Giant Axonal Neuropathy (GAN) is a rare and debilitating inherited condition that generally appears in early childhood. It is caused by mutations in the GAN gene that encodes gigaxonin, a member of the BTB/kelch superfamily of cytoskeletal proteins. Gigaxonin has now been identified as a ubiquitin-scaffolding protein that is essential for neuronal function and survival through its control of the degradation of the light chain of microtubule-associated protein 1B. This is of particular interest since alterations in the cytoskeletal network are also a feature of more common diseases such as amyotrophic lateral sclerosis, so knowledge of the function of gigaxonin may provide insights into the pathogenesis of neurodegenerative disorders in general. Giant Axonal Neuropathy (GAN) is a devastating sensory and motor Neuropathy caused by mutations in the GAN gene, which encodes the ubiquitously expressed protein gigaxonin1,2,3,4,5. Cytopathological features of GAN include Axonal degeneration, with accumulation and aggregation of cytoskeletal components6,7. Little is currently known about the molecular mechanisms underlying this recessive disorder. Here we show that gigaxonin controls protein degradation, and is essential for neuronal function and survival. We present evidence that gigaxonin binds to the ubiquitin-activating enzyme E1 through its amino-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of microtubule-associated protein 1B (MAP1B)8. Overexpression of gigaxonin leads to enhanced degradation of MAP1B-LC, which can be antagonized by proteasome inhibitors. Ablation of gigaxonin causes a substantial accumulation of MAP1B-LC in GAN-null neurons. Moreover, we show that overexpression of MAP1B in wild-type cortical neurons leads to cell death characteristic of GAN-null neurons, whereas reducing MAP1B levels significantly improves the survival rate of null neurons. Our results identify gigaxonin as a ubiquitin scaffolding protein that controls MAP1B-LC degradation, and provide insight into the molecular mechanisms underlying human neurodegenerative disorders.