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A. Thiadens, S. Roosing, C. B. Hoyng, J. J. C. van Lith-Verhoeven, L. I. van den Born, A. I. den Hollander, F. P. M. Cremers, C. C. W. Klaver; Expanding the Phenotypic Consequences of the CNGB3 Gene: Mutations Cause Progressive Cone Dystrophy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3096.
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Mutations in the CNGB3 and CNGA3 genes have been shown to be an important cause of achromatopsia, a congenital cone dysfunction syndrome. We investigated whether these genes are also involved in the later onset progressive cone dystrophy (PCD).
We identified 60 patients with PCD using standard clinical criteria. Patients did not have nystagmus, had initially a normal visual acuity, and had documented proof of decreasing cone function during the second or third decade. Inheritance was autosomal recessive or sporadic. All patients were screened for CNGB3 mutations by sequence analysis; a subset of 27 patients was additionally analysed for CNGA3 mutations. Parents of patients were tested for carriership when appropriate.
CNGA3 sequence analysis revealed no pathologic variants in the 27 patients. Mutations in the CNGB3 gene were present in 3/60 (5%) patients. We identified a compound heterozygous 11-bp deletion in exon 7 (p.R296fsX) with a 3’ splice site mutation in intron 8 (c.991-3T>G); a compound heterozygous 8-bp deletion (p.P273fsX) in exon 6 with a stop mutation in exon 7 (p.R296fsX); and a homozygous missense mutation in exon 11 (p.R403Q). The latter variant had not been detected in ethnically matched control persons, suggesting a pathogenic mutation. The tested parents were heterozygous for one mutation and had no clinical phenotype of PCD. Phenotypes of these patients showed an initially absent macular reflex progressing to a bulls eye maculopathy later in life. ERGs performed over time showed clear evidence of progressive deterioration of cone responses; rod responses remained normal.
Only the CNGB3 gene appears to cause PCD in a proportion of patients. It remains intriguing why a combination of CNGB3 protein truncating mutations leads to PCD in some cases, but, as previously shown by others, to achromatopsia in other cases.
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