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S. Thiagalingam, T. L. McGee, R. G. Weleber, M. A. Sandberg, K. M. Trzupek, M. O. Sweeney, E. L. Berson, T. P. Dryja; Mutations in the KCNV2 Gene in Patients With Cone Dystrophy and a Supernormal Rod Electroretinogram. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1657.
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Mutations in KCNV2 a gene encoding a voltage gated K+ channel subunit were identified by another group as a molecular cause of cone dystrophy with markedly reduced visual acuity, a subnormal rod electroretinogram (ERG) at low flash intensities, and a supernormal rod ERG at high flash intensities (Wu H et al. Am J Hum Genet 2006;79:574-579). We screened this gene in patients with this subtype of retinal dystrophy to see if our patients had mutations in this gene.
We evaluated leukocyte DNA from 7 unrelated patients with this condition. The 2 exons and flanking intron DNA of KCNV2 were amplified using 4 primer pairs and PCR. Direct sequencing in both forward and reverse directions was performed. The DNA of 95 controls was also screened.
In one family both the proband and her affected sister were found to be compound heterozygotes with a c.778T substitution resulting in a K260X (AAG to TAG) nonsense mutation, and a c.1637C substitution in the stop codon resulting in the addition of 60 amino acids at the end of the protein (X546QextX61; TAG to CAG). Two unaffected siblings and the father of these patients had the K260X mutation but no other changes. Another patient carried two adjacent mutations c.721T and c.722A. Analysis of her mother’s DNA showed the same mutations indicating that the changes were in cis and resulted in a stop codon (P241X; CCG to TAG). A second change was not identified in this patient. Patients from 4 other unrelated families were heterozygotes with the same c.1381A substitution resulting in G461R (GGA to AGA). All 4 patients had different second missense changes (c.533T, P178L; c.638C, R213P; c.592A, C198S; and c.473G, F158C). The 7th patient was a homozygote with c.1348G, W450G (TGG to GGG). None of these 9 changes was found in 95 controls.
KCNV2 mutations account for most if not all cases of cone dystrophy with a supernormal rod ERG. Nearly half of the pathogenetic mutations reported by others and identified thus far by our group are nonsense or no-stop mutations or are deletions, suggesting loss-of-function alleles are the underlying cause of this phenotype.
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