Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation

Mahammad, Saleemulla; Murthy, S. N. Prasanna; Didonna, Alessandro; Grin, Boris; Israeli, Eitan; Perrot, Rodolphe; Bomont, Pascale; Julien, J.P.; Kuczmarski, Edward R.; Opal, Puneet; Goldman, Robert D.

doi:10.1172/jci66387

Cited by 113 publications

(175 citation statements)

References 79 publications

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“…It is a predicted E3 ligase adaptor protein believed to flag substrates for ubiquination on the proteasome 17 . Recent studies also suggest that disturbed cytoskeletal regulation, likely involving the proteasome degradation pathway 18 , is responsible for the formation of aggregates of some type 3 and type 4 intermediate filament proteins, which is a morphological characteristic of this disease, and many others.…”

Section: Introductionmentioning

confidence: 99%

“…Using three cellular models, Mahammad et al 18 showed that restoring functional gigaxonin in cultured cells had a direct impact on vimentin, peripherin and NF-L. Using GAN patient fibroblasts, they were able to clear the vimentin aggregates by expressing wild type (WT) gigaxonin.…”

Section: Introductionmentioning

confidence: 99%

“…Lastly, using a human neuroblastoma cell line, SH-SY-5Y that stably expresses WT gigaxonin, they revealed clearance of NF-L protein by both immunoblotting and immunofluorescence. Since their manuscript 18 was accepted for publication, the Goldman and Opal laboratories have obtained evidence that gigaxonin also regulates the turnover of glial fibrillary acidic protein (GFAP) in astrocytes (Dr. Robert Goldman, Northwestern University Feinberg School of Medicine, personal communication).…”

Section: Introductionmentioning

confidence: 99%

“…However, there are two confirmed GAN cases with straight hair, further suggesting CMT as a differential diagnosis for GAN 21 . Some pathological factors in GAN, like NF-L and peripherin accumulation, are also hallmarks of many other diseases 22 including Alexander disease (AxD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, neuronal IF inclusion disease (NIFID), diabetic neuropathy, spinal muscular atrophy (SMA), and some forms of CMT (such as CMT 2E) 18, 23 . Thankfully, basic cellular biology research has caught up with clinical research for GAN.…”

Section: Introductionmentioning

confidence: 99%

“…Thankfully, basic cellular biology research has caught up with clinical research for GAN. Patient cerebrospinal fluid (CSF) samples that have been collected over the past three years can finally be used in pilot studies now that putative surrogate biomarkers have finally been elucidated 18 .…”

Section: Introductionmentioning

confidence: 99%

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Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

et al. 2014

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

et al. 2014

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Giant axonal neuropathy (GAN) in an 8‐year‐old girl caused by a homozygous pathogenic splicing variant in GAN gene

Guo

Su²,

Zhu

et al. 2021

American J of Med Genetics Pt A

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Giant axonal neuropathy (GAN) is a progressive disease that involves the peripheral and central nervous systems. This neurodegenerative disease is caused by variants in the GAN gene encoding gigaxonin, and is inherited in an autosomal recessive manner. Herein, we performed whole‐exome sequencing on a 8‐year‐old child with dense, curly hair, weakness in both lower limbs, and abnormal MRI. The child was born to consanguineous parents. Our results revealed that the child carried the c.1373+1G>A homozygous pathogenic variant of the GAN gene, while both parents were heterozygous carriers. According to the validation at the cDNA levels, the splicing variant led to the skipping of exon 8 and affected the Kelch domain's formation. Unlike the previously reported cases of GAN, the child's clinical manifestations revealed peripheral nervous system involvement, no vertebral signs, cerebellar signs, and spasticity, but only MRI abnormalities. These results suggested that the patient's central nervous system was mildly involved, which may be related to the genotype. In order to further clarify the correlation between GAN genotype and phenotype, combined with this patient, 54 cases of reported homozygous variants of the GAN gene were merged for the analysis of genotype and phenotype. The results revealed a certain correlation between the GAN gene variant domain and the patient's clinical phenotype, such as central nervous system involvement and age of onset.

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Animal models and therapeutic prospects for Charcot–Marie–Tooth disease

Bouhy

Timmerman

2013

Annals of Neurology

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Charcot-Marie-Tooth (CMT) neuropathies are inherited neuromuscular disorders caused by a length-dependent neurodegeneration of peripheral nerves. More than 900 mutations in 60 different genes are causative of the neuropathy. Despite significant progress in therapeutic strategies, the disease remains incurable. The increasing number of genes linked to the disease, and their considerable clinical and genetic heterogeneity render the development of these strategies particularly challenging. In this context, cellular and animals models provide powerful tools. Efficient motor and sensory tests have been developed to assess the behavioral phenotype in transgenic animal models (rodent and fly). When these models reproduce a phenotype comparable to CMT, they allow therapeutic approaches and the discovery of modifiers and biomarkers. In this review, we describe the most convincing transgenic rodent and fly models of CMT and how they can lead to clinical trial. We also discuss the challenges that the research, the clinic, and the pharmaceutical industry will face in developing efficient and accessible treatment for CMT patients.

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Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation

Abstract: Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN

Cited by 113 publications

References 79 publications

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

Giant axonal neuropathy (GAN) in an 8‐year‐old girl caused by a homozygous pathogenic splicing variant in GAN gene

Animal models and therapeutic prospects for Charcot–Marie–Tooth disease

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