Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1)

Department of Ophthalmology , University of Groningen, Groningen, Groningen, Netherlands
Nature Genetics (Impact Factor: 29.35). 01/2004; 35(4):318-21. DOI: 10.1038/ng1261
Source: PubMed

ABSTRACT Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

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    • "The coiled-coil region of the kinesin protein may interact with another kinesin protein, resulting in homo- or heterodimerization to facilitate movement in pair form. Mutation in either of these regions may thus result in the inability of dimer formation or the inability to interact effectively with microtubules, and thus the inability to deliver cargo [3]. A second mechanistic hypothesis involves the inability of mutated KIF21A to move in and out of an active state, resulting in the inability to deliver cargo [3,27]. "
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    ABSTRACT: To describe the phenotypic characteristics and clinical course of a sporadic case of congenital fibrosis of the extraocular muscles (CFEOM) and Möbius syndrome with a de novo mutation in the KIF21A gene encoding a kinesin motor protein. An individual with the rare combination of CFEOM and Möbius syndrome underwent comprehensive ophthalmologic and neurological evaluations. Magnetic resonance imaging (MRI) including diffusion tensor imaging (DTI) tractigraphy at 3T field strength was used to evaluate orbital, encephalic, and intracranial nerve integrity. The proband and her healthy parents underwent screening for mutations in the KIF21A, PHOX2A, and TUBB3 genes. The patient exhibited congenital, nonprogressive, bilateral external ophthalmoplegia, bilateral ptosis, bilateral facial palsy, and developmental delay. Her inability to blink resulted in severe exposure keratopathy and subsequent corneal perforation requiring a penetrating keratoplasty. MRI revealed an unremarkable configuration of the axial central nervous system and preservation of the intracranial portion of cranial nerves I, II, III, V, VI, VII, and VIII (cranial nerve IV is not normally visualized by MRI). A novel and de novo heterozygous KIF21A mutation (c.1056C>G, p.Asp352Glu) in a highly conserved region of the gene was present in the proband. The reported KIF21A D352E mutation and associated phenotype further expand the clinical and mutational spectrum of CFEOM and Möbius syndrome.
    Molecular vision 03/2014; 20:368-75. · 1.99 Impact Factor
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    • "Recently, the TUBB2B E421K substitution was also identified as a cause of CFEOM [10]. Among the mutations identified in KIF21A, the p.R954W mutation is a hotspot, accounting for about 72% to 75% of patients with CFEOM1 [5,11]. However, the mechanism underlying the high frequency of this mutation is poorly understood. "
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    ABSTRACT: To identify the causative mutation with its possible origin in a Chinese family with congenital fibrosis of extraocular muscles type 1 (CFEOM1) and to characterize the ocular phenotypes and lesions in the corresponding intracranial nerves. Three affected siblings and their asymptomatic parents underwent comprehensive ophthalmic examinations and neuropathologic analysis involving magnetic resonance imaging (MRI). KIF21A, PHOX2A, and TUBB3 genes were sequenced on the leukocyte-derived DNA to detect variants. The disease-linked haplotype was analyzed using four microsatellite markers across the KIF21A locus. All three affected individuals displayed typical CFEOM1. MRI revealed complicated but consistent neuromuscular abnormalities in the two patients examined, including hypoplastic oculomotor nerves, complete absence of bilateral superior rectus muscles, and unilateral absence of the abducens nerve with marked atrophy of the corresponding lateral rectus muscle. A heterozygous hotspot mutation KIF21A c.2860C>T was identified in all patients, but it was absent in both parents. Haplotype analysis of the disease locus showed the likely maternal inheritance of the disease-associated haplotype to all three affected offspring, strongly suggesting maternal germline mosaicism of the mutation. Germline mosaicism of KIF21A c.2860C>T is likely to cause the high occurrence of this mutation in the population. This information may be useful for genetic counseling. KIF21A mutations can affect the abducens nerve and cause complete absence of the bilateral superior rectus muscles. MRI characterization of new CFEOM1 phenotypes would assist clinical management.
    Molecular vision 01/2014; 20:15-23. · 1.99 Impact Factor
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    • "They transfected cultured hippocampal neurons with 14 different mutant ß-tubulins (highlighted in Figure 3) and found that two of them, TUBB3E410K and TUBB3D417H, suppressed anterograde axonal cargo transport as well as the ability of type 1, 3 and 4 kinesins (that is, major players in axonal transport) to move to axon tips. Of these, the type 4 kinesin KIF21A is of particular interest: it acts as a genuine axonal transporter [43] and its mutations have been linked to type 1 congenital fibrosis of the extraocular muscles (CFEOM), a pathology that affects nerve growth to certain eye muscles [44]. The TUBB3E410K and TUBB3D417H mutations cause a very similar pathology (type 3 CFEOM) [25], suggesting that these mutations functionally relate to KIF21A in vivo. "
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    ABSTRACT: The hallmarks of neurons are their slender axons which represent the longest cellular processes of animals and which act as the cables that electrically wire the brain, and the brain to the body. Axons extend along reproducible paths during development and regeneration, and they have to be maintained for the life time of an organism. Both axon extension and maintenance essentially depend on the microtubule (MT) cytoskeleton. For this, MTs organise into parallel bundles that are established through extension at the leading axon tips within growth cones, and these bundles then form the architectural backbones, as well as the highways for axonal transport essential for supply and intracellular communication. Axon transport over these enormous distances takes days or even weeks and is a substantial logistic challenge. It is performed by kinesins and dynein / dynactin, which are molecular motors that form close functional links to the MTs they walk along. The intricate machinery which regulates MT dynamics, axonal transport and the motors is essential for nervous system development and function, and its investigation has huge potential to bring urgently required progress in understanding the causes of many developmental and degenerative brain disorders. During the last years new explanations for the highly specific properties of axonal MTs and for their close functional links to motor proteins have emerged, and it has become increasingly clear that motors play active roles also in regulating axonal MT networks. Here, I will provide an overview of these new developments. includes: Table of Drosophila MT motor proteins ( PDF link:
    Neural Development 09/2013; 8:17. DOI:10.1186/1749-8104-8-17 · 3.45 Impact Factor
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