CNGA3 Mutations in Hereditary Cone Photoreceptor Disorders

Abstract

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. We now report the results of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorders. 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. In total, mutations were identified in 53 independent families comprising 38 new CNGA3 mutations, in addition to the 8 mutations 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 were identified in six additional families. 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. The missense mutations mostly affect amino acids conserved among the members of the cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasmic 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 detected 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 Scandinavia and northern Italy, have a common origin.

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene

“…Thus far, complete ophthalmological examination indicated that electroretinographic analysis remains the most reliable method for complete achromatopsia diagnosis. 14 The identification of the novel mutation p.Arg313X in GNAT2 gene together with the report of a previous Tunisian sporadic case carrying a homozygous P372S mutation in CNGA3 gene, 18 highlights the genetic heterogeneity of the ACH in Tunisian population. These findings further delineate the genetic heterogeneity of rare autosomal recessive diseases in Tunisia, as reported previously for different conditions.…”

“…Genetic analysis to the CNGA3, CNGB3 and PDE6C genes As a sporadic Tunisian achromatopsia case has been reported with p.Pro372Ser mutation within CNGA3 gene, 18 patient ACH4 from family ACH1-G, was screened for this mutation. Direct sequencing of exon 7 excluded the p.Pro372Ser mutation in that patient.…”

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

“…[37][38][39] The CNGA3 and CNGB3 subunits are structurally similar, being composed of six transmembrane domains (S1-S6), a pore-forming region, a cyclic nucleotide-binding domain and a C-linker region (Figure 4a). While CNGA3 alone is sufficient to form functional CNG channels in heterologous expression systems, CNGB3 requires co-expression of the CNGA3 subunit.…”

“…40,41 Although 81 different variants of CNGA3 have been documented to date, only 2 known (Figure 4a) of the CNGA3 protein. 38 The p.(Cys319Arg) allele segregating in family PKAB157 is the first homozygous missense variant located in the S5 region (Figure 4a). The results of our in vitro functional characterizations support the pathogenic nature of p.Cys319Arg change, which might not mediate any cone function under physiological conditions.…”

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

“…2,3 In other populations, CNGA3-associated ACHM seems to be more prevalent. 4,5 CNGA3 and CNGB3 mutations result in a loss of cone photoreceptor function in humans and in animals with mutations in the homologous genes.…”