A Novel kif21a Mutation in a Patient With Congenital Fibrosis of the Extraocular Muscles and Marcus Gunn Jaw-Winking Phenomenon

Abstract

Objective: To determine whether congenital fibrosis of the extraocular muscles (CFEOM) with Marcus Gunn jaw-winking phenomenon (MG) can result from mutations in the KIF21A gene encoding a kinesin motor protein.Methods: An individual with CFEOM1 (classic autosomal dominant CFEOM) and MG underwent a comprehensive ophthalmic examination. He and his healthy parents underwent screening for mutations in the KIF21A gene by direct DNA sequencing. The clinical records of our previously described patients with CFEOM and KIF21A mutations were reviewed for evidence of more extensive dysinnervation.Results: A de novo and novel KIF21A mutation 2840T→C (M947T) was present in the proband. In ad-dition, among our previously described patients with CFEOM and KIF21A mutations, 3 individuals had MG and 1 had hypertropia during toothbrushing.Conclusions: This report introduces a new CFEOM1 KIF21A mutation and is, to our knowledge, the first report of a genetic defect associated with MG. The combination of CFEOM1 with MG supports a primary neurogenic etiology of CFEOM resulting from KIF21A mutations.Clinical Relevance: These findings will increase understanding of the etiology of CFEOM and increase awareness of the affiliation of CFEOM with MG.

The Genetic Basis of Complex Strabismus

“…Interestingly, despite the large size of KIF21A-the gene contains 38 exons and encodes a 1674 amino acid protein-we have identified only seven different pathogenic mutations (37,39). All seven are missense mutations and several alter the same or adjacent nucleotides, resulting in only four amino acid residue substitutions.…”

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).…”