Recurrent Mutation of the KIF21A Gene in Japanese Patients with Congenital Fibrosis of the Extraocular Muscles

Shimizu, Satoko; Okinaga, A; Maruo, T

doi:10.1007/s10384-005-0243-7

Cited by 16 publications

(5 citation statements)

References 16 publications

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“…All seven mutations in KIF21A identified to date in CFEOM1 patients are concentrated in three exons (exons 8, 20, and 21), and the mutation detection rate by scanning of these exons is about 97–98% [Yamada et al, 2003; Andrews et al, 2006]. Among these mutations, R954W is the most prevalent worldwide [Yamada et al, 2003; Tiab et al, 2004; Lin et al, 2005], and it has been found in some Japanese families [Shimizu et al, 2005]. In our family, all affected individuals showed an inability to elevate the eyes above the horizontal line with aberrant eye movements on attempted upgaze.…”

Section: Discussionmentioning

confidence: 99%

“…To date, four subtypes have been recognized: CFEOM1, CFEOM2, CFEOM3, and Tukel syndrome [Andrews et al, 2006]. Genotype–phenotype correlations have been increasingly elucidated since mutations in PHOX2A and KIF21A were found to be associated with the CFEOM2 and CFEOM1 phenotypes, respectively [Nakano et al, 2001; Yamada et al, 2003, 2004, 2005; Tiab et al, 2004; Lin et al, 2005; Shimizu et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

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Congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with progressive cerebellar ataxia

Yoshida

Okano

Hoshi

et al. 2007

American J of Med Genetics Pt A

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We here report on a Japanese family with congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with slowly progressive cerebellar ataxia. The pedigree indicated autosomal dominant inheritance. All affected individuals showed a complete loss of upgaze function with ptosis, and severe or moderate restriction of downgaze function probably from the birth. Horizontal gaze function was well preserved, except for the eldest patient, who showed both eyes almost totally fixed in exotrophic position. The primary vertical and horizontal position of each eye varied from patient to patient. Aberrant eye movements were observed on attempted upgaze. They showed amblyopia and/or astigmatism, but none of them complained of diplopia. Pupillary reactions were normal, and retinal pigmentary degeneration or optic atrophy was not observed. These ophthalmological findings were consistent with the CFEOM phenotype. The two middle-aged patients, but not the two younger patients, showed slowly progressive gait ataxia with juvenile onset. Magnetic resonance images of the brain indicated cerebellar atrophy in addition to congenital hypoplasia in the cerebellar vermis. Molecular genetic analysis provided a negative linkage to the FEOM3 locus. Linkage to the FEOM1 locus could not be excluded in our family, but mutation in KIF21A, a major cause of the CFEOM1 phenotype, was not detected. We consider that this family may broaden the spectrum of the clinical features of CFEOM or the related disorders presenting with the CFEOM phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with progressive cerebellar ataxia

Yoshida

Okano

Hoshi

et al. 2007

American J of Med Genetics Pt A

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“…Remarkably, only 8 unique mutations altering only 4 amino acids have been identified among the 56 CFEOM1 and 3 CFEOM3 probands harboring KIF21A mutations reported to date by us [6-8] and by others [13-16]. Three of these amino acid residues are located in heptad repeats within the third coiled-coil region of the KIF21A stalk, and one of these, R954, is altered in ≥ 86% of all individuals with KIF21A mutations reported to date.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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.

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“…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). …”

Section: Congenital Fibrosis Of the Extraocular Muscles Type Imentioning

confidence: 99%

Human Genetic Disorders of Axon Guidance

Engle

2010

Cold Spring Harbor Perspectives in Biology

189

223

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Recurrent Mutation of the KIF21A Gene in Japanese Patients with Congenital Fibrosis of the Extraocular Muscles

Cited by 16 publications

References 16 publications

Congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with progressive cerebellar ataxia

Congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with progressive cerebellar ataxia

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

Human Genetic Disorders of Axon Guidance

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