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Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia.

Brémond-Gignac D, Bitoun P, Reis LM, Copin H, Murray JC, Semina EV - Mol. Vis. (2010)

Bottom Line: None of the observed sequence alterations were found in normal controls.The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers.The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Ophthalmology, St Victor University Hospital of Amiens, INSERM UMRS968, Vision Institute, Paris VI University, Amiens, France.

ABSTRACT

Purpose: Aniridia and congenital cataract represent rare but severe developmental ocular conditions. We examined 33 probands from France for mutations in several transcription factors associated with these phenotypes, the forkhead box E3 (FOXE3), paired box gene 6 (PAX6), paired-like homeodomain transcription factor 2 (PITX2), and paired-like homeodomain transcription factor 3 (PITX3) genes.

Methods: Out of 33 probands, 27 were affected with congenital cataract while the remaining six were affected with aniridia (with or without cataract). The coding regions of FOXE3, PAX6, PITX2, and PITX3 were examined by direct DNA sequencing of gene-specific PCR products.

Results: A novel dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract. Another novel FOXE3 sequence change, c.571-579dup (p.Tyr191_Pro193dup), was identified in a patient with aniridia, mild lens opacities, and some additional ocular defects; this patient was also found to carry a nonsense mutation in PAX6. PAX6 mutations were identified in two additional probands with aniridia and cataracts. None of the observed sequence alterations were found in normal controls. No mutations were identified in PITX2 or PITX3.

Conclusions: The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers. The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles. The p.Tyr191_Pro193dup is predicted to result in an in-frame duplication of three amino acids; however, the contribution of this mutation to the phenotype is unclear since the affected patient also carries a nonsense mutation in PAX6 which acts upstream of FOXE3 in the molecular pathway. The identified PAX6 mutations correspond to the two most commonly observed mutant alleles and demonstrate phenotypes that are consistent with the previously reported spectrum.

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Related in: MedlinePlus

Novel FOXE3 mutations. Fragments of DNA sequence trace chromatograms corresponding to the c.959G>C (p.X320SerextX73) mutation in Patient 1(A) and the c.571–579dup (p.Tyr191_Pro193dup) variant in Patient 2 (B). Mutation sites indicated with arrows.
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f1: Novel FOXE3 mutations. Fragments of DNA sequence trace chromatograms corresponding to the c.959G>C (p.X320SerextX73) mutation in Patient 1(A) and the c.571–579dup (p.Tyr191_Pro193dup) variant in Patient 2 (B). Mutation sites indicated with arrows.

Mentions: Screening of FOXE3 identified a mutation in the stop codon of FOXE3, c.959G>C (p.X320SerextX72), in Patient 1 with congenital cataract (Figure 1A). There was no family history of ocular disease and no other family members were available for testing. The mutation results in a change of the termination codon into serine leading to the addition of 72 erroneous amino acids to the end of the protein. No other changes in FOXE3 were identified in this patient. A second sequence alteration in FOXE3 was identified in Patient 2 affected with aniridia, corneal limbal insufficiency, nystagmus, severe axile myopia, mild lens opacities, and development of a fibrous posterior capsular reaction after lens surgery (Figure 2). This FOXE3 variant, c.571–579dup (p.Tyr191_Pro193dup), results in an in-frame duplication of 3 amino acids (Figure 1B and Figure 3A). The same patient was later found to also carry a PAX6 mutation (see below). the parents of Patient 2 appear to be unaffected but were not available for testing. Neither of the identified FOXE3 variants was seen in 182 Caucasian control individuals nor the previously reported 332 controls of mixed ethnicity [7].


Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia.

Brémond-Gignac D, Bitoun P, Reis LM, Copin H, Murray JC, Semina EV - Mol. Vis. (2010)

Novel FOXE3 mutations. Fragments of DNA sequence trace chromatograms corresponding to the c.959G>C (p.X320SerextX73) mutation in Patient 1(A) and the c.571–579dup (p.Tyr191_Pro193dup) variant in Patient 2 (B). Mutation sites indicated with arrows.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927439&req=5

f1: Novel FOXE3 mutations. Fragments of DNA sequence trace chromatograms corresponding to the c.959G>C (p.X320SerextX73) mutation in Patient 1(A) and the c.571–579dup (p.Tyr191_Pro193dup) variant in Patient 2 (B). Mutation sites indicated with arrows.
Mentions: Screening of FOXE3 identified a mutation in the stop codon of FOXE3, c.959G>C (p.X320SerextX72), in Patient 1 with congenital cataract (Figure 1A). There was no family history of ocular disease and no other family members were available for testing. The mutation results in a change of the termination codon into serine leading to the addition of 72 erroneous amino acids to the end of the protein. No other changes in FOXE3 were identified in this patient. A second sequence alteration in FOXE3 was identified in Patient 2 affected with aniridia, corneal limbal insufficiency, nystagmus, severe axile myopia, mild lens opacities, and development of a fibrous posterior capsular reaction after lens surgery (Figure 2). This FOXE3 variant, c.571–579dup (p.Tyr191_Pro193dup), results in an in-frame duplication of 3 amino acids (Figure 1B and Figure 3A). The same patient was later found to also carry a PAX6 mutation (see below). the parents of Patient 2 appear to be unaffected but were not available for testing. Neither of the identified FOXE3 variants was seen in 182 Caucasian control individuals nor the previously reported 332 controls of mixed ethnicity [7].

Bottom Line: None of the observed sequence alterations were found in normal controls.The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers.The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Ophthalmology, St Victor University Hospital of Amiens, INSERM UMRS968, Vision Institute, Paris VI University, Amiens, France.

ABSTRACT

Purpose: Aniridia and congenital cataract represent rare but severe developmental ocular conditions. We examined 33 probands from France for mutations in several transcription factors associated with these phenotypes, the forkhead box E3 (FOXE3), paired box gene 6 (PAX6), paired-like homeodomain transcription factor 2 (PITX2), and paired-like homeodomain transcription factor 3 (PITX3) genes.

Methods: Out of 33 probands, 27 were affected with congenital cataract while the remaining six were affected with aniridia (with or without cataract). The coding regions of FOXE3, PAX6, PITX2, and PITX3 were examined by direct DNA sequencing of gene-specific PCR products.

Results: A novel dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract. Another novel FOXE3 sequence change, c.571-579dup (p.Tyr191_Pro193dup), was identified in a patient with aniridia, mild lens opacities, and some additional ocular defects; this patient was also found to carry a nonsense mutation in PAX6. PAX6 mutations were identified in two additional probands with aniridia and cataracts. None of the observed sequence alterations were found in normal controls. No mutations were identified in PITX2 or PITX3.

Conclusions: The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers. The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles. The p.Tyr191_Pro193dup is predicted to result in an in-frame duplication of three amino acids; however, the contribution of this mutation to the phenotype is unclear since the affected patient also carries a nonsense mutation in PAX6 which acts upstream of FOXE3 in the molecular pathway. The identified PAX6 mutations correspond to the two most commonly observed mutant alleles and demonstrate phenotypes that are consistent with the previously reported spectrum.

Show MeSH
Related in: MedlinePlus