Giant axonal neuropathy (GAN): Case report and two novel mutations in the gigaxonin gene

Kuhlenbäumer, Gregor; Young, Peter; Oberwittler, C.; Hünermund, G.; Schirmacher, Anja; Domschke, Katharina; Ringelstein, Bernd; Stögbauer, Florian

doi:10.1212/wnl.58.8.1273

Cited by 54 publications

(35 citation statements)

References 10 publications

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“…With the mutations reported in the present study, the total number of GAN mutations identified amounts 24, found in 20 families of various origins Kuhlenbaumer et al, 2002). We report here the first deletions of the GAN gene and the first mutations in exons 4 and 6, and Kuhlenbäumer and colleagues reported the first mutation in exon 8.…”

Section: Resultssupporting

confidence: 63%

Identification of seven novel mutations in theGAN gene

et al. 2003

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Giant axonal neuropathy (GAN) is a severe early onset neurodegenerative disorder affecting both the peripheral nerves and the central nervous system. The diagnosis is based on the presence of characteristic giant axons on nerve biopsy. In GAN, the integrity of the intermediate filament network is altered. Indeed, abnormal accumulation of the intermediate filaments has been reported in different cell types, including in the swollen axons, which are filled with neurofilaments. We identified the defective protein, gigaxonin, of unknown function, and reported fourteen distinct mutations in twelve families of various origins. Two additional mutations have been recently reported. In the present study, we analysed the GAN gene in 6 families, and identified seven novel mutations: three nonsense and two missense mutations and two deletions. In addition, the molecular result for an already reported family was re-evaluated. In this family, the R269Q "polymorphism" is in fact the pathogenic mutation.

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Section: Resultssupporting

confidence: 63%

Identification of seven novel mutations in theGAN gene

et al. 2003

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“…However, a number of single amino acid mutations of this protein are clearly associated with giant axonal neuropathy (23,51,52). Due to the relevance of these mutations to human disease, we provide a brief overview of their predicted structural context in the GAN1 ␤-propeller (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of the Kelch Domain of Human Keap1

Zhang

Hannink

et al. 2004

Journal of Biological Chemistry

198

181

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Keap1 is a substrate adaptor protein for an ubiquitin ligase complex that targets the Nrf2 transcription factor for degradation. Keap1 binds Nrf2 through its C-terminal Kelch domain, which contains six copies of the evolutionarily conserved kelch repeat sequence motif. The structure of the Kelch domain from human Keap1 has been determined by x-ray crystallography to a resolution of 1.85 Å. The Kelch domain forms a 6-bladed ␤-propeller structure, with residues at the C terminus forming the first strand in the first blade. Key structural roles have been identified for the highly conserved glycine, tyrosine, and tryptophan residues that define the kelch repeat sequence motif. In addition, we show that substitution of a single amino acid located within a loop that extends out from the bottom of the ␤-propeller structure abolishes binding of Nrf2. The structure of the Kelch domain of Keap1 represents a high quality model for the superfamily of eukaryotic kelch repeat proteins and provides insight into how disease-causing mutations perturb the structural integrity of the Kelch domain.

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“…Notably, an insertion mutation at the 6th amino acid (A6ins) causes a frame shift resulting in premature termination at the 8th amino acid, implicating it as a functionally disruptive mutation. Kuhlenbäumer et al [3] reported a mutation that caused a change of isoleucine to threonine at A423 that may cause a mild subclinical neuropathy in heterozygous individuals, revealed by abnormal nerve conduction velocities [3].…”

Section: Geneticsmentioning

confidence: 99%

Giant axonal neuropathy

Yang

Allen

Ding

et al. 2007

Cell. Mol. Life Sci.

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Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder affecting both the central and peripheral nervous systems. Cytopathologically, the disorder is characterized by giant axons with derangements of cytoskeletal components. Geneticists refined the chromosomal interval containing the locus, culminating in the cloning of the defective gene, GAN. To date, many distinct mutations scattered throughout the coding region of the locus have been reported by researchers from different groups around the world. GAN encodes the protein, gigaxonin. Recently, a genetic mouse model of the disease was generated by targeted disruption of the locus. Over the years, the molecular mechanisms underlying GAN have attracted much interest. Studies have revealed that gigaxonin appears to play an important role in cytoskeletal functions and dynamics by directing ubiquitin-mediated degradations of cytoskeletal proteins. Aberrant accumulations of cytoskeletal-associated proteins caused by a defect in the ubiquitin-proteasome system (UPS) have been shown to be responsible for neurodegeneration occurring in GAN-null neurons, providing strong support for the notion that UPS plays crucial roles in cytoskeletal functions and dynamics. However, many key questions about the disease remain unanswered.

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Giant axonal neuropathy (GAN): Case report and two novel mutations in the gigaxonin gene

Cited by 54 publications

References 10 publications

Identification of seven novel mutations in theGAN gene

Identification of seven novel mutations in theGAN gene

Crystal Structure of the Kelch Domain of Human Keap1

Giant axonal neuropathy

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