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

Yamada, Koki; Andrews, Caroline; Chan, Wai Man; McKeown, Craig A.; Magli, Adriano; Berardinis, Teresa de; Loewenstein, Anat; Lazar, Moshé; O’Keefe, Michael; Letson, Robert D.; London, Arnold; Ruttum, Mark S.; Matsumoto, Naomichi; Saito, Nakamichi; Morris, Lisa; Monte, Monte A. Del; Johnson, Roger H.; Uyama, Eiichiro; Houtman, W. A.; Vries, Berendina De; Carlow, Thomas J.; Hart, Blaine L.; Krawiecki, Nicolas; Shoffner, John M.; Vogel, Melina; Katowitz, James A.; Goldstein, Scott; Levin, Alex V.; Şener, Emin Cumhur; Öztürk, Bayram; Akarsu, Ayşegül; Brodsky, Michael C.; Hanisch, Frank; Cruse, Robert P.; Zubcov, Alina A.; Robb, Richard M.; Roggenkäemper, Peter; Gottlob, Irène; Kowal, Lionel; Battu, Ravi; Traboulsi, Elias I.; Franceschini, P; Newlin, Anna; Demer, Joseph L.; Engle, Elizabeth C.

doi:10.1038/ng1261

Cited by 238 publications

(210 citation statements)

References 13 publications

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“…Among the six genes deleted in Case 1 only, KIF21A is known to be mutated in patients with CFEOM type 1 (CFEOM1, OMIM #135700) (Yamada et al 2003). Thus, CFEOM observed in Case 1 may be accounted for by the lack of KIF21A due to the deletion.…”

Section: Resultsmentioning

confidence: 99%

Phenotype–genotype correlation in two patients with 12q proximal deletion

et al. 2004

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Proximal 12q deletion is a very rare chromosomal abnormality. Only five cases have been reported. Among the five, an Argentinian patient (Case 1) with del(12)(q11q13) and a Japanese patient (Case 2) with del(12)(q12q13.12) were analyzed because they shared several clinical features: growth and psychomotor developmental delay; strabismus; broad and short nose with anteverted nostrils; high, arched palate; large, lowset ears; widely set nipples; short fingers and clinodactyly of fifth fingers; and abnormality of the second and third toes. To clarify the correlation between the deleted genes and their phenotypes, we delimited their deleted regions by fluorescence in situ hybridization (FISH). The overlapped region in the deletions spanned 6.2 Mb where at least 15 genes were predicted to localize on the current human genome database. Among them, YAF2 and AMIGO2 were the most plausible candidates to affect growth and psychomotor retardation, respectively, in both cases. 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.

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Section: Resultsmentioning

confidence: 99%

Phenotype–genotype correlation in two patients with 12q proximal deletion

et al. 2004

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“…The amplicons were subjected to analysis by denaturing high-performance liquid chromatography (DHPLC) using a nucleic acid fragment analysis system (WAVE; Transgenomic, Inc., Omaha, NE) and/or to direct DNA sequencing on an ABI 377 DNA sequencer (Applied Biosystems, Foster City, CA) as previously described. 7 The PCR sequencing and DHPLC primers and conditions are available on request. The three PHOX2A exons and flanking intron-exon boundaries were similarly amplified using our published primer sets 10 and these amplicons were directly sequenced.…”

Section: Methodsmentioning

confidence: 99%

“…We have demonstrated that in most pedigrees CFEOM1 maps to the FEOM1 locus on chromosome 12cen, [3][4][5][6] and results from recurrent heterozygous mutations in a developmental kinesin, KIF21A. 7 Similar to other members of the kinesin superfamily, mouse Kif21a is a motor protein engaged in anterograde axonal transport. 8 We have identified six different pathogenic KIF21A mutations in 44 (98%) of 45 CFEOM1 probands.…”

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Identification ofKIF21AMutations as a Rare Cause of Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3)

Yamada

Chan

Andrews

et al. 2004

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G3 A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C3 T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A.CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. 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. (Invest Ophthalmol Vis Sci.

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“…15 KIF21A gene mutations have been identified in patients with CFEOM type 1, which shows an autosomal dominant trait and is associated with the absence of the superior branch of the oculomotor nerve. 16 ARIX (PHOX2A) gene mutations have been found in patients with CFEOM type 2, which shows an autosomal recessive trait and is proposed to result from aberrant development of the oculomotor and trochlear nerve, and nuclei in the brainstem. 17 On the basis of working hypothesis that idiopathic superior oblique muscle palsy might be a clinically milder variant of CFEOM type 2, we previously analyzed ARIX and PHOX2B gene polymorphisms in patients with idiopathic superior oblique muscle palsy.…”

Section: Introductionmentioning

confidence: 99%

Phenotype–phenotype and genotype–phenotype correlations in patients with idiopathic superior oblique muscle palsy

et al. 2011

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Idiopathic superior oblique muscle palsy presents, as quantitative phenotypes, vertical deviation and cyclodeviation in eye alignment on clinical testing, and superior oblique muscle hypoplasia on imaging. We determined ARIX and PHOX2B polymorphisms as genotypes, and analyzed phenotype-phenotype and genotype-phenotype correlations in 37 patients with idiopathic superior oblique muscle palsy. Vertical deviations were measured at upright position of the head and head tilt for 301 to either side, and angles of objective excyclodeviations were determined by image analysis on fundus photographs. Crosssectional areas of the superior oblique muscle near the eye globe-optic nerve junction were measured by image analysis on coronal sections of magnetic resonance imaging to calculate the paretic-side/normal-side ratios. Among the phenotypes, the increase in vertical deviations elicited by head tilt to the paretic side, the decrease in vertical deviations elicited by head tilt to the normal side and the difference of angles of objective excyclodeviations between the paretic side and normal side were significantly correlated inversely with the paretic-side/normal-side ratios of the cross-sectional areas of the muscle (r¼À0.43 with P¼0.0084, r¼À0.34 with P¼0.038, and r¼À0.43 with P¼0.009, respectively, n¼37, Pearson's correlation test). Fifteen patients with ARIX and/or PHOX2B polymorphisms had significantly greater paretic-side/normal-side ratios of the muscle compared with 20 patients without the polymorphisms (P¼0.017, n¼35, Mann-Whitney U-test). The patients with ARIX and/or PHOX2B polymorphisms had less hypoplastic superior oblique muscles.

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

Cited by 238 publications

References 13 publications

Phenotype–genotype correlation in two patients with 12q proximal deletion

Phenotype–genotype correlation in two patients with 12q proximal deletion

Identification ofKIF21AMutations as a Rare Cause of Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3)

Phenotype–phenotype and genotype–phenotype correlations in patients with idiopathic superior oblique muscle palsy

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