Alexander Disease: Screening and in silico functional characterization of variants on candidate gene

BackgroundAlexander disease is a rare neurological ailment caused by the degeneration of the white matter of the brain accompanied with the formation of Rosenthal fibers, a unique cytoplasmic inclusion within astrocytes (non-nerve tissue) in the brain. Till to date only heterozygous de novo mutation in Glial Fibrillary Acidic Protein (GFAP) gene is found to be associated for the disease phenotype. Methods and Resultthe aim of our study was to determine the genetic basis of an Indian-origin juvenile AxD patient with pathological symptoms of macrocephaly and psychomotor delay followed by regression, spastic parapresis and feeding difficulty. The patient was screened for mutation in candidate gene for AxD by Whole Exome Sequencing and the detected variants were further reconfirmed by Sanger sequencing. The clonicopathological feature were investigated and two heterozygous missence variants (c.983T>C and c. 626G>A) were indentify in GFAP gene of the patient. Familial screenings of both of these variants were predicted to be pathogenic or damaging by various in silico methods and prediction tools. ConclusionThis altered GFA protein get accumulated in cytoplasm of the astroglial cells, leading to formation of Rosenthal fibers, which impairs cell function. Future study, however, would be helpful to understand the functional mechanism of these variant in formation of Rosenthal fibers leading to AxD pathophysiology.