Disease relevance of CNGA3

• The patients presented with a clinical picture typical for congenital achromatopsia and there was no significant difference in the phenotype of subjects with either CNGA3 or CNGB3 mutations based on standard ophthalmological examination [1].

High impact information on CNGA3

• We report the identification of missense mutations in CNGA3 in five families with RM [2].
• Recently, a suitable candidate gene, CNGA3, encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel, a key component of the phototransduction pathway, has been cloned and assigned to human chromosome 2q11 (refs 3,4) [2].
• Cone photoreceptor cyclic nucleotide-gated (CNG) channels are thought to be tetrameric assemblies of CNGB3 (B3) and CNGA3 (A3) subunits [3].
• In contrast, we discovered that channels formed by CNGA3 subunits from cone photoreceptors were unaffected by PIP(3) [4].
• CNGA3 mutations were detected not only in patients with the complete form of achromatopsia but also in incomplete achromats with residual cone photoreceptor function and (rarely) in patients with evidence for severe progressive cone dystrophy [5].

Biological context of CNGA3

• PCR/RFLP analysis and DNA sequencing was applied for mutation screening of CNGA3 and CNGB3 [1].
• However, we assume residual cone function in a subject homozygous for the Phe547Leu mutation in CNGA3 based on prior detailed psychophysical testing (i.e., dark adaptation and spectral luminosity) [1].
• We recently showed that mutations in the CNGA3 gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11 [5].
• The majority of all known CNGA3 mutations (39/46) are amino acid substitutions compared with only four stop-codon mutations, two 1-bp insertions and one 3-bp in-frame deletion [5].
• Radiation hybrid mapping of the CNGA3 gene encoding the alpha-subunit of the cGMP gated cation channel in human cone photoreceptors resulted in a maximum lod score of 16.1 with marker D2S2311 combined with a calculated physical distance of 6.19cR10,000 [6].

Anatomical context of CNGA3

• To investigate the functional consequences of these mutations, we expressed mutant human CNGA3 subunits in Xenopus oocytes, alone or together with human CNGB3, and studied these channels using patch-clamp recording [7].
• METHODS: RT-PCR was used to amplify full length open reading frames of CNGA3 from human testes RNA and to detect and distinguish among splice forms in 23 tissues [8].
• However, non-human homologs of CNGA3 have been cloned from a variety of other tissues including kidney, heart, pineal gland, adrenal gland and testes [8].
• The phenotypic characteristics of cpfl1 mice are similar to those observed in patients with complete achromatopsia (ACHM2, OMIM 216900) and the cpfl1 mutation is the first naturally-arising mutation in mice to cause cone-specific photoreceptor function loss. cpfl1 mice may provide a model for congenital achromatopsia in humans [9].

Associations of CNGA3 with chemical compounds

• Our results show that SCH 51866 and sildenafil are antagonists of a Ca(2+)-permeable channel (CNGA3) and that both compete with cGMP for a regulatory site of Ca(2+)-influx in D. discoideum [10].

Physical interactions of CNGA3

• Studies using chimeric channels revealed that transplantation of the pore domain from CNGA2 was sufficient to confer high affinity PsTx binding upon a CNGA3 background [11].

Other interactions of CNGA3

• Since mutations in the CNGA3 gene may cause a variety of retinal dystrophies (complete and incomplete achromatopsia and progressive cone dystrophy), GNAT2 mutations may also prove to be implicated in other forms of retinal dystrophy with cone dysfunction [12].
• These data indicate that the CNGA3 gene maps within the critical interval of the ACHM2 locus for rod monochromacy and thus is a candidate gene for this disease [6].
• Screening of the CEPH YAC library and subsequent STS mapping indicated the physical order cen-D2S2222-D2S2175-(D2S2187/D2S2311)-qtel ofmarkers on 2q11 and showed that the CNGA3 gene maps most closely to D2S2187 and D2S2311 [6].
• The results suggest that CNG4 forms functional heterooligomeric channels with CNG3 in vitro and probably also in intact tissues [13].
• The usefulness of the compounds for physiological studies under nondamaging light conditions was examined in HEK293 cells expressing the alpha subunit of the cyclic-nucleotide-gated (CNG) channel of cone photoreceptors (CNGA3) and of olfactory neurons (CNGA2) by using confocal laser scanning microscopy and the patch clamp technique [14].

Analytical, diagnostic and therapeutic context of CNGA3

• Immunoprecipitation experiments showed association of hCNGA3 subunit with both of wild-type and mutant hCNGB3 subunits [15].

References