Analysis of FOXD3 sequence variation in human ocular disease.
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PURPOSE: The migratory neural crest cell population makes a significant contribution to the anterior segment structures of the eye. Consequently, several anterior segment dysgenesis phenotypes are associated with mutations in genes expressed during neural crest development. The forkhead box D3 (FOXD3) gene encodes a forkhead transcription factor that plays an important role in neural crest specification in vertebrates and therefore may be involved in human eye disease. METHODS: We screened 310 probands with developmental ocular conditions for variations in FOXD3. RESULTS: Six nonsynonymous FOXD3 variants were identified. Four of these changes, c.47C>T (p.Thr16Met), c.359C>T (p.Pro120Leu), c.517A>C (p.Asn173His), and c.818_829dup (p.Arg273_Gly276dup), affected conserved regions and were observed primarily in probands with aniridia or Peters anomaly; out of these four variants, one, p.Arg273_Gly276dup, was not detected in control populations and two, p.Pro120Leu and p.Asn173His, were statistically enriched in cases with aniridia or Peters anomaly. The p.Arg273_Gly276dup variant was seen in a proband with aniridia as well as two additional unrelated probands affected with anophthalmia or congenital cataracts. The p.Asn173His variant affects Helix 2 of the DNA-binding domain and was observed in two unrelated patients with Peters anomaly or aniridia; in both cases, one parent carried the same allele. CONCLUSIONS: FOXD3 variants increase the risk of anterior segment dysgenesis phenotypes in humans. The p.Asn173His mutation affects a residue in the forkhead domain that is 100% conserved among vertebrate orthologs and is predicted to participate in protein-protein interactions. Its phenotypic effects may be modulated by transcriptional cofactors which have yet to be identified. (+info)
Mutation analysis of PAX6 in inherited and sporadic aniridia from northeastern China.
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PURPOSE: Haplo-insufficiency at the paired box gene 6 (PAX6) locus causes aniridia,which is characterized by iris hypoplasia and other anterior and posterior eye defects leading to poor vision. This study aimed to identify novel PAX6 mutations that lead to familial and sporadic aniridia in northeastern China. METHODS: Two aniridia patients from a family and a sporadic patient underwent full ophthalmologic examinations. Genomic DNA was isolated from the affected individuals, 5 noncarriers in the family and 100 healthy normal controls. The coding regions and the adjacent intronic sequence of PAX6 were amplified by polymerase chain reaction (PCR) and direct bidirectional sequencing. RESULTS: A nonsense mutation in exon 9 (c.718C>T) was identified in the patients but not in any other unaffected families. A C>T substitution at codon 240 converts an arginine codon (CGA) to a termination codon (TGA).The same mutation was detected in the sporadic patient by chance. CONCLUSIONS: A mutation in the PAX6 gene was confirmed to be capable of causing the classic aniridia phenotype. This is the first report on the "hotspot" c.718C>T transition from northeastern Chinese families. (+info)
Bilateral traumatic expulsive aniridia after phacoemulsification.
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PAX6 mutations identified in 4 of 35 families with microcornea.
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PURPOSE: Mutations in paired box gene 6 (PAX6) are the major cause of aniridia that may associate with several other developmental anomalies of the eye, including microcornea in rare cases. However, systemic evaluation of PAX6 in patients with microcornea as the major sign has not been reported. This study aims to detect PAX6 mutations in patients with microcornea. METHODS: Genomic DNA of probands was prepared from 35 families with microcornea. The coding regions of PAX6 were screened by Sanger sequencing and novel variations were further evaluated in 192 normal individuals. Bioinformatics analysis was used to evaluate the structural consequences related to the pathology of the mutations. RESULTS: The average corneal horizontal diameter of the 35 probands is 8.03 +/- 1.27 mm (the median value is 8 mm). Among them, eight patients presented with normal iris, one had aniridia, and different severities of iris hypoplasia were detected in the rest. In four probands, three heterozygous variations in PAX6 were identified: a novel c.83_85delAGA (p.Lys28del) in two families; a novel c.337G>C (p.Ala113Pro) in one family; and a known c.399_399+5del6 in one family. None of the variations were detected in 192 normal individuals. Two of the four probands had partial iris while the other two presented with full iris. CONCLUSIONS: We identified two novel and a known mutation of PAX6 in four probands with microcornea, accounting for 11.4% of microcorneas in this cohort. The findings not only expand the spectrum of PAX6 mutations, but also suggest that PAX6 mutations may be a common cause of microcornea. (+info)
Rapid visualisation of microarray copy number data for the detection of structural variations linked to a disease phenotype.
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PAX6 analysis of two sporadic patients from southern China with classic aniridia.
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PURPOSE: To investigate the paired box 6 (PAX6) gene in two sporadic patients from southern China presenting with classic aniridia. METHODS: The two sporadic patients underwent complete physical and ophthalmic examinations. Genomic DNA was extracted from the leukocytes of the peripheral blood collected from the families of the two sporadic patients and 100 unrelated control subjects from the same population. Exons 4-13 of PAX6 were amplified by polymerase chain reaction (PCR) and sequenced directly. The ophthalmic examinations included best-corrected visual acuity, slit-lamp examination, fundus examination, optical coherence tomography, and Pentacam and Goldmann perimetry. RESULTS: The two patients were affected with aniridia accompanied by nystagmus. A heterozygous PAX6 frameshift mutation in exon 7, c.375_376delAG (p.Arg125SerfsX7), was identified in sporadic patient 1 and not in any of the unaffected family members and normal controls. One novel mutation in exon 10, c.868_871dupAGTT (p.Phe291X), was detected in sporadic patient 2. The frameshift mutation we identified has not previously been reported either in China or abroad. CONCLUSIONS: Although PAX6 mutations and polymorphisms have been reported in various ethnic groups, we report, for the first time, the identification of one new PAX6 mutation in Chinese aniridia patient. (+info)