The KIF21A gene spans 150 kilobases of genomic DNA and consists of 38 exons encoding an amino acid 1674 protein, which is part of the kinesin superfamily involved in transportation of vesicles and organelles.9,20,21 Its N terminal kinesin motor domain interacts with microtubules and tends to be highly conserved,19 the coiled-coil domain is important for dimer formation, and the tail with 7 WD40 repeats is assumed to interact with the presently unidentified cargo based on functional study of another kinesin family member KIF21B.21 Despite the large size of KIF21A, only a small number of different mutations have been reported. Nine of the 11 published mutations were found in families with the CFEOM1 phenotype (1067T>C, 2830G>C, 2839A>G, 2840 T>G, 2840T>C, 2861G>A, 2861G>T, 3022G>C, 3029T>C), 1 was identified in a CFEOM3 kindred (2841G>A), and 1 has been associated with both CFEOM1 and CFEOM3 (2860C>T).6,9,10,18,19Figure 2 illustrates the known KIF21A mutations, including those described herein.6,9,10,15- 19 Intriguingly, 10 of the published mutations are clustered, resulting in substitutions of 5 amino acid residues in the coiled-coil region (944Glu, 947Met, 954Arg, 1008Ala, 1010Ile), and the 11th mutation, involving amino acid 356 at the α-helix 6 of the KIF21A motor domain, is close to the neck-linker region, which is located between the motor domain and the coiled-coil region. Because the C terminal of α-helix 6 is the base of the neck linker, it has been proposed that all these reported mutations could impair protein dimerization and thus interfere with the transportation of cargos from the oculomotor neurons to the synapse of the developing neuromuscular junction of the extraocular muscle.22 By contrast, the novel mutation reported herein, 84C>G, is located in exon 2, which encodes the beginning of the kinesin motor domain. This finding would further support a role for dysfunction of the kinesin motor domain in the etiology of CFEOM because the previous mutation 356M>T was close to the linker region and could have interfered with its function. Point mutations affecting motor domains of other kinesin family genes have been reported in spastic paraplegia (KIF5A) and Charcot-Marie-Tooth disease (KIF1Bβ) and have been shown to prevent stimulation of the motor adenosine triphosphatase by microtubule binding.23,24 Furthermore, specific point mutations in kinesin motor orthologs have been associated with loss of kinesin motor function.25- 27 Whether the KIF21A mutation identified herein, 84C>G, could interfere with motor function through similar mechanisms remains to be determined.