De novo mutations in GFAP cause Alexander disease: clinical features,
fMRI and functional analysis
Abstract
Two de novo mutations in GFAP gene were identified
(c.214G>A, p.E72K and c.1235C>T, p.T412I) by
whole exome sequencing. The common clinical features of the two patients
was bulbar dysfunction, pyramidal signs and white matter lesions in
periventricular regions. We conducted a novel data-driven method to
explore the atrophic pattens and spontaneous brain functional network
activity according to the neuroimaging data. Similar atrophic patterns,
increased brain functional connectivity in occipital and posterior
parietal cortex were detected in the two probands. Western blotting
revealed the decreased level of GFAP with p.T412I mutation, while p.E72K
and p.R239C mutations were at a similar level to wild type, suggesting
the mutations located in the tail domain could decrease the solubility
of GFAP. Abnormal inclusions of mutant GFAP were colocalized with
ubiquitin, 20S proteasome, protein 1 light chain 3-II (LC3-II) and
lysosome. The mutant GFAP caused activated autophagy flux while
ubiquitin-proteasome pathway could be blocked as a mechanism for
degrading aggregates.We herein presented two AxD patients with
heterozygous mutations in GFAP. We noticed that mutant GFAP aggregations
induced activated autophagy upon proteasome degrading pathway
impairment. Our findings further expand the clinical and genetic
spectrum of AxD.