CNGA3 mutations in hereditary cone photoreceptor disorders

We recently showed that mutations in the CNGA3 gene encoding the alpha -sub unit of the cone photoreceptor cGMP-gated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11. We now report the result s of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorde rs. CNGA3 mutations were detected not only in patients with the complete fo rm of achromatopsia but also in incomplete achromats with residual cone pho toreceptor function and (rarely) in patients with evidence for severe progr essive cone dystrophy. In total, mutations were identified in 53 independen t families comprising 38 new CNGA3 mutations, in addition to the 8 mutation s reported elsewhere. Apparently, both mutant alleles were identified in 47 families, including 16 families with presumed homozygous mutations and 31 families with two heterozygous mutations. Single heterozygous mutations wer e identified in six additional families. The majority of all known CNGA3 mu tations (39/46) are amino acid substitutions compared with only four stop-c odon mutations, two 1-bp insertions and one 3-bp in-frame deletion. The mis sense mutations mostly affect amino acids conserved among the members of th e cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasm ic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP- binding domain. Several mutations were identified recurrently (e.g., R277C, R283W, R436W, and F547L). These four mutations account for 41.8% of all de tected mutant CNGA3 alleles. Haplotype analysis suggests that the R436W and F547L mutant alleles have multiple origins, whereas we found evidence that the R283W alleles, which are particularly frequent among patients from Sca ndinavia and northern Italy, have a common origin.