Disease relevance of KIF21A

• Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3) [1].
• In addition, among our previously described patients with CFEOM and KIF21A mutations, 3 individuals had MG and 1 had hypertropia during toothbrushing [2].
• Eighteen affected individuals had congenital bilateral ptosis and restrictive infraductive (downward) ophthalmoplegia, consistent with the published descriptions of classic CFEOM families linked to the CFEOM1 locus [3].
• Main outcome measure: Presence or absence of mutation in PHOX2A gene in two siblings with exotropia and recessive CFEOM [4].
• METHODS: Clinical examination of one patient with CFEOM1, one family with clinical features of CFEOM2, one family with recessive CFEOM3, one family with horizontal gaze palsy and progressive scoliosis (HGPPS), and four patients with various combinations of congenital cranial nerve abnormalities [5].

High impact information on KIF21A

• Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1) [6].
• We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A [6].
• Despite the amino acid sequence similarity between KIF21A and KIF21B, these proteins localize differently to dendrites and axons [7].
• We now have mapped a variant of CFEOM, exotropic strabismus fixus ("CFEOM2") [8].
• Comparing clinical and MRI phenotypes did not reveal distinguishing features among KIF21A mutations [9].

Biological context of KIF21A

• Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype [1].
• CONCLUSIONS: Orbital imaging in CFEOM1 due to various amino acid substitutions in the kinesin KIF21A demonstrates consistent abnormalities of motor and sensory innervation in the orbit [9].
• METHODS: Linkage analysis with microsatellite markers at chromosome 12q and direct sequence analysis of the KIF21A gene were performed on three families and one sporadic CFEOM case [10].
• METHODS: Mutational analysis was carried out by direct automated sequencing of the PCR products from exons 8, 20, and 21 of the KIF21A gene [11].
• We have previously determined that a CFEOM1 gene maps to the FEOM1 locus on chromosome 12cen [12].

Anatomical context of KIF21A

• KIF21A protein is localized throughout neurons, while KIF21B protein is highly enriched in dendrites [7].
• The authors have previously demonstrated that CFEOM1 results from a developmental absence of the superior division of the oculomotor nerve [13].
• A Japanese family with FEOM1-linked congenital fibrosis of the extraocular muscles type 1 associated with spinal canal stenosis and refinement of the FEOM1 critical region [14].

Associations of KIF21A with chemical compounds

• Direct DNA sequence analysis identified a 2860C-->T change in exon 21, resulting in a tryptophan substitution for arginine in codon 954 of KIF21A [15].

Other interactions of KIF21A

• This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3 [1].
• Regarding unique symptoms in each case, congenital fibrosis of the extraocular muscles found only in Case 1 may be caused by KIF21A deletion and hearing loss and cleft palate in Case 2 by COL2A1 defect [16].
• Sequencing of the sarcospan gene in CFEOM1 patients from 6 families revealed no mutations [17].
• Genetic analysis revealed linkage to the FEOM1 locus with a maximum lod score of 4.42 at theta of zero [14].
• Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve [15].

Analytical, diagnostic and therapeutic context of KIF21A

• Sequence analysis disclosed a heterozygous c.2860C>T mutation in the KIF21A gene in all families and in the sporadic case [10].
• METHODS: Setting: Institutional practice. patient population:Six members of an Iranian family with CFEOM underwent complete ocular examinations including assessment of ocular motility, visual acuity, slit-lamp biomicroscopy, tonometry, and ophthalmoscopy [4].
• DNA typing for linkage to the FEOM1 (12p11.2-q12) and FEOM3 (16qter) loci was performed on genomic DNA, using fluorescent microsatellite polymorphic markers [14].

References