Biochemical and Biophysical Research Communications, Vol.386, No.4, 639-644, 2009
A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is associated with heterozygous mutations in the KIF21A gene, including a major (R954W) and a minor (M947T) mutation. Kank1, which regulates actin polymerization, cell migration and neurite outgrowth, interacted with the third and fourth coiled-coil domains of KIF21A protein at its ankyrin-repeat domain. While both KIF21A R954W and KlF21A(M947T) enhanced the formation of a heterodimer with the wild type, KIF21A(WT), these mutants also enhanced the interaction with Kank1. Knockdown of KIF21A resulted in Kankl predominantly occurring in the cytosolic fraction, while KIF21A(WT) slightly enhanced the translocation of Kankl to the membrane fraction. Moreover, KIF21A(R954W) significantly enhanced the translocation of Kankl to the membrane fraction. These results suggest that KlF21A regulates the distribution of Kankl and that KIF21A mutations associated with CFEOM1 enhanced the accumulation of Kankl in the membrane fraction. This might cause an abrogation of neuronal development in cases of CFEOM1 through over-regulation of actin polymerization by Kank1. (C) 2009 Elsevier Inc. All rights reserved.