Learn about KIF21A
Kinesins are family of molecular motor proteins found in many cell types. In neurons, they are responsible for anterograde axonal transport of organelles, protein complexes, and mitochondria from the neuron cell body down the axon to the synapse. These kinesin molecules have a motor at one end that interacts with tubulin and 'walks' down the microtubule tract within an axon. At the other end, the kinesin molecules have a cargo loading area, where they interact with the cargo they transport. In the middle of the molecule is the flexible stalk, connecting the motor to the cargo regions. Different kinesin molecules have different cargo loading regions, specific for the cargo they are designed to transport.
In 2003 we identified the deveopmental kinesin KIF21A as the CFEOM1 disease gene.
Below is the predicted structure of KIF21A.
The motor domain is blue, the cargo loading region, made up of seven WD40 repeats in the tail, is green, and the stalk is grey. Within the stalk are three coiled-coil regions indicated in yellow. Two alternatively spliced regions in the stalk are white. The locations of pathogenic (disease causing) mutations are shown in color as red triangles. Five are located in the third coiled-coil region and one is at the end of the motor domain. Non-pathogenic polymorphisms that we have identified are shown as blue dots, and are in the stalk outside of a coiled-coil region.
In human fetal tissue, a Northern blot analysis shows that KIF21A mRNA is abundant in the brain with lower levels in liver and kidney.
The picture below shows RT-PCR analysis of this protein's expression (undertaken using northern-blot hybridization) and revealed abundant expression in most of the central nervous system, with primary expression in the brain and lower levels in heart, skeletal muscle and kidney.
We believe that CFEOM1 is probably caused by the inability of mutated KIF21A to deliver a cargo that is necessary for the development of oculomotor axons, extraocular muscles and the neuromuscular junction. We are currently working to identify what the cargo and its interacting proteins are and hope to gain further understanding of the role of this kinesin in cranial nerve and extraocular muscle development.
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Yamada K, Andrews C, Chan WM, McKeown CA, Magli A, de Berardinis T, Loewenstein A, Lazar M, O'Keefe M, Letson R, London A, Ruttum M, Matsumoto N, Saito N, Morris L, Del Monte M, Johnson RH, Uyama E, Houtman WA, de Vries B, Carlow TJ, Hart BL, Krawiecki N, Shoffner J, Vogel MC, Katowitz J, Goldstein SM, Levin AV, Sener EC, Ozturk BT, Akarsu AN, Brodsky MC, Hanisch F, Cruse RP, Zubcov AA, Robb RM, Roggenkaemper P, Gottlob I, Kowal L, Battu R, Traboulsi EI, Franceschini P, Newlin A, Demer JL, Engle EC. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet. 2003 Dec;35(4):318-21. Epub 2003 Nov 02.
Yamada K, Chan WM, Andrews C, Bosley TM, Sener EC, Zwaan JT, Mullaney PB, Ozturk BT, Akarsu AN, Sabol LJ, Demer JL, Sullivan TJ, Gottlob I, Roggenkaemper P, Mackey DA, De Uzcategui CE, Uzcategui N, Ben-Zeev B, Traboulsi EI, Magli A, de Berardinis T, Gagliardi V, Awasthi-Patney S, Vogel MC, Rizzo JF 3rd, Engle EC. Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3). Invest Ophthalmol Vis Sci. 2004 Jul;45(7):2218-23. http://www.iovs.org/cgi/content/full/45/7/2218