Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1

Abstract

BackgroundCongenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A.ResultsSixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands.ConclusionAnalysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.

Interaction of brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 and kinesin motor protein KIF21A

“…Single amino acid mutations in the coiled-coil stalk of KIF21A have been identified in patients with congenital fibrosis of the extraocular muscles types 1 and 3. These conditions are autosomal dominant congenital disorders with strabismus that appears to result from abnormal development of ocular nuclei and nerves (26,27).…”

Human Genetic Disorders of Axon Guidance

“…Eighty mutation-positive patients of multiple ethnicities reported to date harbor only 11 unique missense mutations, which are often de novo, and 75% harbor 2860C.T (R954W). These mutations alter only seven of the 1675 amino acids in KIF21A, of which five are located in the third coiled-coil domain of the KIF21A stalk and two in the motor domain (Yamada et al 2003;Ali et al 2004;Tiab et al 2004;Lin et al 2005;Shimizu et al 2005;Yamada et al 2005;Zhang et al 2006;Chan et al 2007;Lu et al 2008;Flaherty et al 2009;Rudolph et al 2009). …”

KIF21A novel deletion and recurrent mutation in patients with congenital fibrosis of the extraocular muscles-1

“…The KIF21 protein is made up of 3 parts: the high conserved kinesin motor domain interacting with microtubules in the N-terminus, the central stalk with 4 coiled-coil regions important for dimer formation, and the tail domain with WD40 repeats in the C-terminus that is responsible for cargo loading. Only 12 missense mutations in KIF21A have been reported (4,5,(8)(9)(10): two of them are located in the motor domain (C28W located in exon2 and M356T located in exon8) and the rest are clustered in the third coiledcoil region (E944Q, M947V, M947R, M947I and M947T in exon20 and R954W, R954Q, R954L, A1008P and I1010T in exon21). Substitution changes may affect the dimer formation of KIF21A (14,15).…”

“…The majority of CFEOM1 patients have symptoms caused by mutation in KIF21A that is located in 12q12 (4). To date, only 12 heterozygous missense mutations of KIF21A have been reported (4,5,(8)(9)(10).…”