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M. Amato, J. L. Tovilla-Canales, M. Aguinaga, H. Perez-Cano, J. C. Zenteno; Molecular Investigation of the CHX10, RAX, OTX2, and SOX2 Genes in Mexican Subjects With Anophthalmia and Microphthalmia. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1317.
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© ARVO (1962-2015); The Authors (2016-present)
Structural congenital malformations of the eye in humans encompass a spectrum of clinically and genetically heterogeneous anomalies such as coloboma, microphthalmia (MO), and anophthalmia (AO). AO, the complete absence of one or both eyes, and MO, eye(s) significantly reduced in size, are severe congenital malformations that occurs with a frequency of 1-2 per 10 000 births. Most cases of non-syndromic MO/AO are sporadic, but families with autosomal recessive, autosomal dominant, or X-linked recessive inheritance have been described. Monogenic forms of isolated MO/AO have been shown to be the result of mutations in genes as CHX10, RAX, OTX2, and SOX2. However, the relative contribution of each of these genes in the disease is not precisely known. Analysis of large groups of MO/AO patients from different populations could help to identify this contribution. In this work we performed the molecular screening of the CHX10, RAX, OTX2, and SOX2 genes in a group of subjects with MO/AO.
We included 14 unrelated probands from Mexican origin with bilateral MO/AO (8 patients) and unilateral MO/AO (6 patients) and contralateral eye defects (eye coloboma, cataract and anterior segment dysgenesis). Complete ophthalmologic examination and genomic DNA analysis were done. The complete coding sequences of CHX10 (5 exons), RAX (2 exons), OTX2 (3 exons), and SOX2 (1 exon) were amplified by PCR and sequenced by the dye terminator method.
SOX2 gene mutations were recognized in two patients (14%), one with bilateral and other with unilateral AO. A same SOX2 c.70del20 deletion was observed in these two unrelated patients. In 4 patients, a heterozygous Asp291Asn mutation was detected; no other CHX10 mutations were detected in these subjects. No RAX gene mutations were observed. A previously described RAX Asp44Glu polymorphism was observed in four subjects. No OTX2 mutations were observed in any patient.
Our results suggest that SOX2 is a major gene in MO/AO pathogenesis; the identification of a same SOX2 deletion in two patients indicates that this alteration is probably related to a specific mutational mechanism. In our sample, no deletereous mutations were detected in RAX and OTX2 genes. Interestingly, four subjects exhibited a same Asp291Asn CHX10 heterozygous mutation, without evidence of a second mutated allele. Further analysis will reveal if this heterozygous CHX10 mutation contributes to the anophthalmic/microphthalmic phenotype.
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