Insights into the role of Filamin A and ARFGEF2 genes in periventricular heterotopia formation
By: by Jason Bennett Neal
Series: Collections of the Harvard University Archives
Published: 2010
Language: eng
Number of pages: 152
Description: Periventricular heterotopia (PH) is a genetic malformation of cerebral cortical development characterized by ectopic neuronal nodules along the lateral ventricles of the brain. The underlying genetic and molecular mechanisms giving rise to this disorder are not well understood. Previous clinical genetic reports have shown that mutations in either Filamin A ( FLNA ) or ADP-ribosylation factor guanine exchange factor 2 ( ARFGEF2 ) genes can cause PH. To reveal insights into the various genetic causes of PH we reported on the extent of a 9.6 Mb terminal deletion in one individual with PH and chromosome 1p36 deletion syndrome. We also reported on the lack of mutations in ASXL2 and KIAA1803 genes in the second known individual with PH and complete agenesis of the corpus callosum. To better understand the genotype-phenotype correlation associated with FLNA gene mutations and PH we reported on two FLNA gene mutations (one is likely non-pathogenic) in two pedigrees associated with PH, mental retardation, and male viability. To reveal insights into the molecular mechanisms underlying PH we examined the potential shared pathway by which FLNA and ARFGEF2 genes lead to PH. FLNA encodes FLNA, a 280 kDa actin binding phosphoprotein which coordinates the reorganization of the cytoskeleton in response to signaling cascades.

ARFGEF2 encodes Brefeldin A-inhibited guanine exchange factor-2 (BIG2), a protein which regulates vesicle trafficking through facilitating GDP-to-GTP exchange of ADP-ribosylation factor 1 (ARF-1). We identified a novel interaction between FLNA and BIG2 proteins by yeasttwo-hybrid, co-immunoprecipitation, and co-localization analysis. We also found that BIG2 (a protein kinase A anchoring protein) does not enhance FLNA (Serine 2152) phosphorylation through anchoring PKA. Rather, FLNA (Serine 2152) phosphorylation regulates BIG2 localization towards the membrane and the apical neuroependymal surface. In addition, FLNA regulates ARF1 activation in response to ephrin-Bl signaling. Finally, we show that the loss of Big2 in Arfgef2 -/- mutant mice causes the loss of neuroependymal adhcrens junctions and PH formation. Overall, these findings suggest that FLNA and BIG2 are involved in a shared molecular pathway regulating the trafficking of adhcrens junction proteins along the neuroependymal surface and the structural integrity of the ventricular lining.
Notes: "August 2010."

Thesis (Ph.D., Division of Medical Sciences (Neurobiology))--Harvard University, 2010.

Includes bibliographical references.