title: A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane.
abstract: 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 KIF21A(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 Kank1 predominantly occurring in the cytosolic fraction, while KIF21A(WT) slightly enhanced the translocation of Kank1 to the membrane fraction. Moreover, KIF21A(R954W) significantly enhanced the translocation of Kank1 to the membrane fraction. These results suggest that KIF21A regulates the distribution of Kank1 and that KIF21A mutations associated with CFEOM1 enhanced the accumulation of Kank1 in the membrane fraction. This might cause an abrogation of neuronal development in cases of CFEOM1 through over-regulation of actin polymerization by Kank1.
authors: Signaling Molecules Research Group, Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
authors: Naoto
authors: N
authors: Kakinuma
authors: Ryoiti
authors: R
authors: Kiyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017089:Ankyrin Repeat / Q000235:genetics; D001763:Blepharoptosis / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins; D005355:Fibrosis; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009801:Oculomotor Muscles / Q000473:pathology*; D009886:Ophthalmoplegia / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D021381:Protein Transport; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C467739:KANK1 protein, human; C119023:KIF21A protein, human; D025521:Tumor Suppressor Proteins; D016547:Kinesins