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

Wang, Panfeng; Li, Shiqiang; Xiao, Xueshan; Guo, Xiangming; Zhang, Qingjiong

doi:10.3892/ijmm.2011.759

Cited by 7 publications

(6 citation statements)

References 17 publications

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“…Twelve heterozygous missense and 1 heterozygous single amino acid deletion account for all KIF21A mutations among the 106 unrelated CFEOM1 probands reported to date (Chan et al, 2007; Lu et al, 2008; Wang et al, 2011). The mutations alter 6 amino acid residues in the 3 rd coiled-coil region of the stalk and 2 residues in the motor domain, and result in indistinguishable phenotypes that are limited to ptosis and ocular dysmotility (Demer et al, 2005; Yamada et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Cheng

Desai

Miranda

et al. 2014

Neuron

110

122

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SUMMARY The ocular motility disorder “Congenital fibrosis of the extraocular muscles type 1″ (CFEOM1) results from heterozygous mutations altering the motor and 3rd coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knock-in mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve’s superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a interacting protein and report that Map1b−/− mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1, and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.

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Section: Introductionmentioning

confidence: 99%

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Cheng

Desai

Miranda

et al. 2014

Neuron

110

122

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“…Notably, all CFEOM1 mutations and a one-residue deletion cluster within a predicted coiled-coil region of the KIF21A stalk or within the motor domain ( Fig. 1 ) 17 . It was shown that a part of the KIF21A stalk containing the residues involved in CFEOM1 ( hs KIF21A aa701-1180, mm KIF21A aa891-1300) binds to its own motor domain, thereby inhibiting the kinesin 12 13 .…”

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confidence: 99%

Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations

Bianchi

Riel

Kraatz

et al. 2016

Sci Rep

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Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.

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“…KIF21A consists of three segments, an N-terminal motor region, a coiled-coil stalk region, and a C-terminal WD40 repeat region [ 37 ]. To date, a total of 12 different missense mutations and one deletion mutation have been detected in CFEOM1 individuals [ 15 – 17 ]. Three KIF21A mutations, c.84C > G (p.C28W), c.1056C > G (p.D352E), and c.1067 T > C (p.M356T), are located in the N-terminal motor region, which interacts with the microtubule track [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…In clinical practice, screening KIF21A gene mutation and investigating genetic etiology for CFEOM patients are helpful to subtype diagnosis. In previous studies, twelve different missense mutations and one deletion mutation were reported in CFEOM1 families [ 15 – 17 ]. Understanding the mutational spectrum of CFEOM patients could benefit mutation screening and guide the directions of basic research in the future.…”

Section: Introductionmentioning

confidence: 99%

Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families

Chen

Huang

Zhang

et al. 2022

Graefes Arch Clin Exp Ophthalmol

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Purpose Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. Methods The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. Results Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. Conclusion Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.

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

Cited by 7 publications

References 17 publications

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations

Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families

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