Hum. Mutat.

SEPT9 is a member of the cytoskeleton-related septin family, which is highly expressed in glia cells in neuronal tissues. Sequence alterations in SEPT9 are known to cause hereditary neuralgic amyotrophy (HNA) but precise cellular consequences have yet to be determined. Since SEPT9 is thought to function through interaction with other septins and small GTPase Rho-mediated signaling, we analyzed the properties of HNA-associated SEPT9 missense variants, SEPT9F (c.278C>T/p.Ser93Phe in SEPT9_v3; NM_006640.3) and SEPT9W (c.262C>T/p.Arg88Trp in SEPT9_v3). We found both sequence variants, but not the wild type, to form filaments with SEPT4 along stress fibers in mesenchymal mouse mammary gland NMuMG cells. In the epithelial cells, the variants, but not the wild type, were colocalized with SEPT11 at cell-cell junctions. In addition, although septin filaments containing SEPT9_v3 were disrupted by Rho/Rhotekin signaling, this was not the case with SEPT9F and SEPT9W. Sequence variations in SEPT9 causing HNA are thus likely to alter modes of interaction with partner molecules in cells, and consequently contribute to the pathogenesis of HNA.

Source:http://purl.uniprot.org/citations/17546647