Edellisen KLHL1 geenin löytöä käsittelevän tekstin sitaatissa oli seuraavat lauseet:
..."The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function in multiprotein complexes through contact sites in their β-propeller domains (14). Recently, a new member of the BTB/Kelch repeat family, gigaxonin (GAN, KLHL16), was reported to be a pathological target for neurodegenerative disorders in which alterations were found to contain multiple mutations in the Kelch repeats in the neurofilament network (15)." tarkistan viitteen 15:
https://www.nature.com/articles/ng1100_370
Published:
The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy
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
disease1,2,3,4.
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 axons5,6.
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 astrocytes7,8,9,10,11. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs12.
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 β-propeller shape13. 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.
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 β-propeller shape13. 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.
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