The protein encoded by the KIF21A gene belongs to a family of plus end-directed kinesins (KIF) that are capable of movement toward opposite ends of the microtubules, thus, providing a solution to the intracellular transport of the neuronal axonal cargo.
Defects in the KIF21A protein are the cause of congenital fibrosis of extraocular muscles-1 (CFEOM1); a congenital ocular motility disorder characterized by restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. Mutations in the same gene are also responsible for another rare form of the disease called CFEOM3.
The KIF21A gene is located on chromosome 12q12. The 38 exons of this gene encode a 1674 amino acid protein. The protein is characterized by an N-terminal motor domain, a coiled-coil stalk domain and a C-terminal WD-40 repeat domain.
To date, about 11 different mutations have been identified in affected patients. Most of these mutations alter the amino acids in the stalk region of the protein, causing changes in the protein's structure, which interferes with its ability to transport cargo within neurons. About 84% of the mutations affect the R954 residue (p.R954W, p.R954Q, and p.R954L; the most common mutation being p.R954W).
Khan et al. (2008) performed amplification refractory mutation system (ARMS) assay to detect the p.R954W mutation of the KIF21A gene in two Saudi families affected with congenital fibrosis of extraocular muscles-1 (CFEOM1). All patients (one child from family A and four adults from family B) were heterozygous for the p.R954W mutation, which is know to affect the development of the superior division of cranial nerve III. Later, Khan et al. (2010) analyzed a family that had familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance. The family consisted of two affected siblings, three asymptomatic siblings, and their two asymptomatic parents. Sequencing of the KIF21A gene revealed heterozygous p.R954L in both affected individuals, but not in their parents or three asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive. Khan et al. (2010) noted that parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. In 2011, Khan et al. sequenced the KIF21A gene in five probands with classic CFEOM1. None of the probands had mutations in KIF21A.
Khan et al. (2011) studied a cohort of ten patients from eight families and ranging from 5–23 years of age. Seven of the eight families were consanguineous. Five patients had Congenital fibrosis of the extraocular muscles1 (CFEOM1) and five had CFEOM3. All patients underwent CFEOM candidate gene testing and a causative mutation, a heterozygous p.R954W change in KIF21A was only found in the one patient from a nonconsanguineous family.