Purpose: To further explore the spectrum of mutations in the Visual System Homeobox 2 (VSX2/CHX10) gene previously found to be associated with autosomal recessive microphthalmia.
Methods: We screened 95 probands with syndromic or isolated developmental ocular conditions (including 55 with anophthalmia/microphthalmia) for mutations in VSX2.
Results: Homozygous mutations in VSX2 were identified in two out of five consanguineous families with isolated microphthalmia. A novel missense mutation, c.668G>C (p.G223A), was identified in a large Pakistani family with multiple sibships affected with bilateral microphthalmia. This p.G223A mutation affects the conserved CVC motif that was shown to be important for DNA binding and repression activities of VSX2. The second mutation, c.249delG (p.Leu84SerfsX57), was identified in an Iranian family with microphthalmia; this mutation has been previously reported and is predicted to generate a severely truncated mutant protein completely lacking the VSX2 homeodomain, CVC domain and COOH-terminal regions.
Conclusions: Mutations in VSX2 represent an important cause of autosomal recessive microphthalmia in consanguineous pedigrees. Identification of a second missense mutation in the CVC motif emphasizes the importance of this region for normal VSX2 function.