Titre
Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Molecular Vision
Auteur(s)
Dansault, A.
Auteure/Auteur
David, G.
Auteure/Auteur
Schwartz, C.
Auteure/Auteur
Jaliffa, C.
Auteure/Auteur
Vieira, V.
Auteure/Auteur
de la Houssaye, G.
Auteure/Auteur
Bigot, K.
Auteure/Auteur
Catin, F.
Auteure/Auteur
Tattu, L.
Auteure/Auteur
Chopin, C.
Auteure/Auteur
Halimi, P.
Auteure/Auteur
Roche, O.
Auteure/Auteur
Van Regemorter, N.
Auteure/Auteur
Munier, F.
Auteure/Auteur
Schorderet, D.
Auteure/Auteur
Dufier, J. L.
Auteure/Auteur
Marsac, C.
Auteure/Auteur
Ricquier, D.
Auteure/Auteur
Menasche, M.
Auteure/Auteur
Penfornis, A.
Auteure/Auteur
Abitbol, M.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1090-0535
Statut éditorial
Publié
Date de publication
2007
Volume
13
Première page
511
Dernière page/numéro d’article
23
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, Non-U.S. Gov't
Résumé
PURPOSE: The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies. METHODS: Patients and related families were ophthalmologically phenotyped, and in some cases neurologically and endocrinologically examined. We screened the PAX6 gene by direct sequencing in three groups of patients: those affected by aniridia; those with diverse ocular manifestations; and those with Peters' anomaly. Two mutations were investigated by generating crystallographic representations of the amino acid changes. RESULTS: Three novel heterozygous mutations affecting three unrelated families were identified: the g.572T>C nucleotide change, located in exon 5, and corresponding to the Leucine 46 Proline amino-acid mutation (L46P); the g.655A>G nucleotide change, located in exon 6, and corresponding to the Serine 74 Glycine amino-acid mutation (S74G); and the nucleotide deletion 579delG del, located in exon 6, which induces a frameshift mutation leading to a stop codon (V48fsX53). The L46P mutation was identified in affected patients presenting bilateral microphthalmia, cataracts, and nystagmus. The S74G mutation was found in a large family that had congenital ocular abnormalities, diverse neurological manifestations, and variable cognitive impairments. The 579delG deletion (V48fsX53) caused in the affected members of the same family bilateral aniridia associated with congenital cataract, foveal hypolasia, and nystagmus. We also detected a novel intronic nucleotide change, IVS2+9G>A (very likely a mutation) in an apparently isolated patient affected by a complex ocular phenotype, characterized primarily by a bilateral microphthalmia. Whether this nucleotide change is indeed pathogenic remains to be demonstrated. Two previously known heterozygous mutations of the PAX6 gene sequence were also detected in patients affected by aniridia: a de novo previously known nucleotide change, g.972C>T (Q179X), in exon 8, leading to a stop codon and a heterozygous g.555C>A (C40X) recurrent nonsense mutation in exon 5. No mutations were found in patients with Peters' anomaly. CONCLUSIONS: We identified three mutations associated with aniridia phenotypes (Q179X, C40X, and V48fsX53). The three other mutations reported here cause non-aniridia ocular phenotypes associated in some cases with neurological anomalies. The IVS2+9G>A nucleotide change was detected in a patient with a microphthalmia phenotype. The L46P mutation was detected in a family with microphthalmia, cataract, and nystagmus. This mutation is located in the DNA-binding paired-domain and the crystallographic representations of this mutation show that this mutation may affect the helix-turn-helix motif, and as a consequence the DNA-binding properties of the resulting mutated protein. Ser74 is located in the PAX6 PD linker region, essential for DNA recognition and DNA binding, and the side chain of the Ser74 contributes to DNA recognition by the linker domain through direct contacts. Crystallographic representations show that the S74G mutation results in no side chain and therefore perturbs the DNA-binding properties of PAX6. This study highlights the severity and diversity of the consequences of PAX6 mutations that appeared to result from the complexity of the PAX6 gene structure, and the numerous possibilities for DNA binding. This study emphasizes the fact that neurodevelopmental abnormalities may be caused by PAX6 mutations. The neuro-developmental abnormalities caused by PAX6 mutations are probably still overlooked in the current clinical examinations performed throughout the world in patients affected by PAX6 mutations.
Sujets
PID Serval
serval:BIB_D53EE0A856A7
PMID
Date de création
2008-01-28T11:59:06.803Z
Date de création dans IRIS
2025-05-20T22:27:14Z
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Nom
BIB_D53EE0A856A7.P001.pdf
Version du manuscrit
preprint
Taille
734.44 KB
Format
Adobe PDF
PID Serval
serval:BIB_D53EE0A856A7.P001
URN
urn:nbn:ch:serval-BIB_D53EE0A856A74
Somme de contrôle
(MD5):e4ba022133b5ec095edeb2e9e6b52406