Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease.

[alexander disease]

Alexander disease (AxD ) is an astrogliopathy that primarily affects the white matter of the central nervous system (CNS ). AxD is caused by mutations in a gene encoding GFAP (glial fibrillary acidic protein ). The GFAP mutations in AxD have been reported to act in a gain-of-function manner partly because the identified mutations generate practically full-length GFAP . We found a novel nonsense mutation (c .1000 â€‰G >T , p .(Glu 312 T er ); also termed p .(E 312 *)) within a rod domain of GFAP in a 67 -year -old Korean man with a history of memory impairment and leukoencephalopathy . This mutation , GFAP p .(E 312 *), removes part of the 2 B rod domain and the whole tail domain from the GFAP . We characterized GFAP p .(E 312 *) using western blotting , in vitro assembly and sedimentation assay , and transient transfection of human adrenal cortex carcinoma SW 13 (Vim (+)) cells with plasmids encoding GFAP p .(E 312 *). The GFAP p .(E 312 *) protein , either alone or in combination with wild-type GFAP , elicited self-aggregation . In addition , the assembled GFAP p .(E 312 *) aggregated into paracrystal-like structures , and GFAP p .(E 312 *) elicited more GFAP aggregation than wild-type GFAP in the human adrenal cortex carcinoma SW 13 (Vim (+)) cells . Our findings are the first report , to the best of our knowledge , on this novel nonsense mutation of GFAP that is associated with AxD and paracrystal formation .European Journal of Human Genetics advance online publication , 23 April 2014 ; doi :10 .1038 /ejhg .2014 .68 .

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Diseases presenting "mutations in axd" symptom

alexander disease

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