Missense Mutation in the Alternative Splice Region of the PAX6 Gene in Eye Anomalies

Azuma, Noriyuki; Yamaguchi, Yuki; Handa, Hiroshi; Hayakawa, Mutsuko; Kanai, Atsushi; Yamada, Masao

doi:10.1086/302529

Cited by 110 publications

(100 citation statements)

References 23 publications

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“…10,11 For example, defects in PITX2 and FOXC1 are associated with Axenfeld-Reiger syndrome and JAG1 with Alagille's syndrome. 2,[10][11][12] Axenfeld-Reiger syndrome is an autosomal dominant condition characterised by iris strands spanning the angle to insert into the prominent Schwalbes line. 10 The PE while often extensive in this condition may only be visible with gonioscopy, or be limited as in the two cases in this study.…”

Section: Resultsmentioning

confidence: 99%

“…1 PE has been found to be present in anything from 8 to 32% of the general population. [1][2][3][4][5] PE occurs in up to 95% of patients with Alagille's syndrome. 6 This has led to the proposal that its presence could be used as a screening tool to aid diagnosis and avoid the need for more invasive tests in children with chronic cholestasis.…”

Section: Introductionmentioning

confidence: 99%

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The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic

Rennie

Chowdhury

Khan

et al. 2004

Eye

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Purpose To estimate the prevalence of posterior embryotoxon (PE) in the general ophthalmic clinic and to identify any features of PE that suggest that it is pathological rather than physiological. Methods Over 700 consecutive patients of all ages were examined with the slit lamp during their routine eye clinic appointment. Patients with posterior embryotoxon were invited to return for full ocular examination including keratometry, corneal topography, and gonioscopy. Results In all, 49 out of 723 patients were found to have PE. This gives a prevalence of 6.8% with an age range of 18 months to 95 years. There was a higher prevalence in the younger age group of 22.5% (age range 18 months to 20 years) compared to 5.9% in the older age range (21-95 years).A total of 29 patients with PE returned for further examination. Six patients had glaucoma (two with Axenfeld's syndrome and one with aniridia), and one had ocular hypertension. In all, 20 patients had bilateral PE on slit-lamp examination, which increased to 24 with gonioscopy. The majority of the PE was seen temporally (97.9%) and limited to a few clock hours. Gonioscopy showed that eight patients with PE had associated inferior pigmentation of schwalbes line. Conclusion This large series found the prevalence of PE the general ophthalmic clinic to be 6.8%. Its presence should prompt careful anterior segment examination, including gonioscopy, to identify any associated abnormalities that may carry a risk of glaucoma. Children should also be assessed for any associated systemic or genetic abnormality.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic

Rennie

Chowdhury

Khan

et al. 2004

Eye

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“…The human PAX6 isoform, and its fly counterparts Ey and Toy, act principally to specify eye fate. Notably, missense mutations of the N-terminal and C-terminal subregion of the paired domain result in distinct ocular disorders in humans: aniridia, the more severe disorder, is often associated with mutations in the C terminus 10,45 . These observations are consistent with the view that the distinct roles of PAX6(5a) and PAX6 proteins shown here are not restricted to D. melanogaster.…”

Section: Discussionmentioning

confidence: 99%

“…These observations are consistent with the view that the distinct roles of PAX6(5a) and PAX6 proteins shown here are not restricted to D. melanogaster. These studies should contribute to our understanding of PAX proteins in dorsal-ventral patterning of the central nervous system, somitogenesis, organogenesis, stem cell biology and human diseases 1,[5][6][7][8][9][10][11][12][13][14][15]45 . Scer\UAS.mg5603 ) and UAS-N ECD (N ECD.Scer\UAS ; two independent insertions on chromosome X and II).…”

Section: Discussionmentioning

confidence: 99%

Growth and specification of the eye are controlled independently by Eyegone and Eyeless in Drosophila melanogaster

et al. 2003

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Control of growth determines the size and shape of organs. Localized signals known as 'organizers' and members of the Pax family of proto-oncogenes are both elements in this control. Pax proteins have a conserved DNA-binding paired domain, which is presumed to be essential for their oncogenic activity. We present evidence that the organizing signal Notch does not promote growth in eyes of D. melanogaster through either Eyeless (Ey) or Twin of eyeless (Toy), the two Pax6 transcription factors. Instead, it acts through Eyegone (Eyg), which has a truncated paired domain, consisting of only the C-terminal subregion. In humans and mice, the sole PAX6 gene produces the isoform PAX6(5a) by alternative splicing; like Eyegone, this isoform binds DNA though the C terminus of the paired domain. Overexpression of human PAX6(5a) induces strong overgrowth in vivo, whereas the canonical PAX6 variant hardly effects growth. These results show that growth and eye specification are subject to independent control and explain hyperplasia in a new way.

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] To date, more than 300 intragenic mutations of the PAX6 have been described. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Most of these mutations are nonsense mutations, frame-shifting insertions or deletion, and splicing mutations, which directly or indirectly introduce premature termination codons (PTCs), and are predominantly associated with AN. 4,5 In contrast, missense mutations usually generate distinctive non-AN phenotypes, including anterior segment anomalies, isolated forveal hypoplasia, and optic nerve malformations.…”

Section: Introductionmentioning

confidence: 99%

Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients

Zhang

Tong

et al. 2011

Eye

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Purpose Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6 (PAX6) gene. The PAX6 gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6 gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations. Patients and methods Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6 gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions.Results By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6 gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C4G (p.Ser119fsX) were identified in the patients of the AN group. A novel missense mutation c.643T4C (p.S216P) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6 gene and DKFZ p686k1684 gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid. Conclusion Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6 gene.

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Missense Mutation in the Alternative Splice Region of the PAX6 Gene in Eye Anomalies

Cited by 110 publications

References 23 publications

The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic

The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic

Growth and specification of the eye are controlled independently by Eyegone and Eyeless in Drosophila melanogaster

Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients

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