Alterations in lipid metabolism gene expression and abnormal lipid accumulation in fibroblast explants from giant axonal neuropathy patients.
BACKGROUND
Giant axonal neuropathy (GAN) is a hereditary neurological disorder that affects both central and peripheral nerves. The main pathological hallmark of the disease is abnormal accumulations of intermediate filaments (IFs) in giant axons and other cell types. Mutations in the GAN gene, encoding gigaxonin, cause the disease. Gigaxonin is important in controlling protein degradation via the ubiquitin-proteasome system. The goal of this study was to examine global alterations in gene expression in fibroblasts derived from newly identified GAN families compared with normal cells.


RESULTS
We report the characterization of fibroblast explants obtained from two unrelated GAN patients. We identify three novel putative mutant GAN alleles and show aggregation of vimentin IFs in these fibroblasts. By microarray analysis, we also demonstrate that the expression of lipid metabolism genes of the GAN fibroblasts is disrupted, which may account for the abnormal accumulations of lipid droplets in these cells.


CONCLUSIONS
Our findings suggest that aberrant lipid metabolism in GAN patients may contribute to the progression of the disease.
Leung
Conrad L
CL
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. cl119@columbia.edu <cl119@columbia.edu>
Pang
Yinghua
Y
Shu
Chang
C
Goryunov
Dmitry
D
Liem
Ronald K H
RK
D000483:Alleles; D001369:Axons / Q000648:ultrastructure; D002460:Cell Line / Q000378:metabolism; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism* / Q000648:ultrastructure; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007382:Intermediate Filaments / Q000737:chemistry / Q000648:ultrastructure; D007438:Introns / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000032:analysis*; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014746:Vimentin / Q000032:analysis
D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D008055:Lipids; D014746:Vimentin