Total colourblindness is caused by mutations in the gene encoding the α-subunit of the cone photoreceptor cGMP-gated cation channel

  title={Total colourblindness is caused by mutations in the gene encoding the $\alpha$-subunit of the cone photoreceptor cGMP-gated cation channel},
  author={Susanne Kohl and Tim Marx and Ian Giddings and Herbert J{\"a}gle and Samuel G. Jacobson and E Apfelstedt-Sylla and Eberhart Zrenner and Lindsay T. Sharpe and Bernd Wissinger},
  journal={Nature Genetics},
Total colourblindness (OMIM 216900), also referred to as rod monochromacy (RM) or complete achromatopsia, is a rare, autosomal recessive inherited and congenital disorder characterized by photophobia, reduced visual acuity, nystagmus and the complete inability to discriminate between colours. Electroretinographic recordings show that in RM, rod photoreceptor function is normal, whereas cone photoreceptor responses are absent. The locus for RM has been mapped to chromosome 2q11 (ref. 2), however… 

CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function.

Foveomacular atrophy can occur in CNGB3-affected subjects, and even heterozygous carriers can exhibit maculopathy, and some retain residual function into middle age and then progressively lose even this remnant.

Genetic basis of total colourblindness among the Pingelapese islanders

It is demonstrated that both α- and β-subunits of the cGMP-gated channel are essential for phototransduction in all three classes of cones.

Achromatopsia caused by novel mutations in both CNGA3 and CNGB3

Current estimates suggest that mutations in CNGB3 account for 40–50% of achromatopsia,14 with mutations inCNGA3 contributing a further 20%.5 There is therefore a significant proportion of patients for whom neither CNGA3 norCNGB3 mutations can be found, and GNAT2 is the third gene to be implicated in achrom atopsia.

Molecular pathogenesis of achromatopsia associated with mutations in the cone cyclic nucleotide-gated channel CNGA3 subunit.

Therapeutic supplementation of the wild type transgene may help correct the visual disorders caused by these two mutations, which appear to induce loss of function by impairing the channel cellular trafficking and plasma membrane targeting.

Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy

A digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation is strongly suggested, with important implications for diagnosis, prognosis, and genetic counseling.

A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene

It is shown that the spontaneous mouse mutant cpfl1 that features a lack of cone function and rapid degeneration of the cone photoreceptors represents a homologous mouse model for PDE6C associated achromatopsia.

Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14

The prevalence of mutations in achromatopsia-causing genes in a cohort of 16 families with both clinical and electrophysiologic evidence consistent with autosomal recessive transmission is investigated, concluding that CNGA3 and CNGB3 mutations are responsible for the substantial majority of achrom atopsia.

Achromatopsia as a potential candidate for gene therapy.

Using adeno-associated virus (AAV)-mediated gene therapy, it is shown that cone function can be restored in all three models and suggests that human achromatopsia may be a good candidate for corrective gene therapy.

Novel homozygous mutation in the alpha subunit of the rod cGMP gated channel (CNGA1) in two Spanish sibs affected with autosomal recessive retinitis pigmentosa

The pathophysiology of RP involves apoptosis of rod cells, and many of the ARRP genes are rod specific, some are only expressed in the retinal pigment epithelium, and none is cone specific.



Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.

It is concluded that the absence or paucity of functional cGMP-gated cation channels in the plasma membrane is deleterious to rod photoreceptors and is an uncommon cause of RP.

Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness

It is speculated that the rod dysfunction in the patient with congenital stationary night blindness is due to an abnormal, continuous activation of transducin by mutant opsin molecules in photoreceptor outer segments.

A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1.

It is proposed that a single base pair missense mutation at codon 99 in exon 2 of this gene generating a tyrosine-to-cysteine change would at least disrupt the EF3handof GCAP1 thereby preventing calcium binding and consequently interfere with activation, and could explain the ultimate demise of cone photoreceptor cells.

Human rod monochromacy: linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2q11.

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.

A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype.

It is shown that the low levels of cGMP in rd chicken retina are a consequence of a null mutation in the photoreceptor guanylate cyclase (GC1) gene, which prevents phototransduction and affects survival of rods and cones but does not interfere with normal Photoreceptor development.

Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling.

A genome-wide search for linkage of achromatopsia to chromosome 2 was performed using an inbred Jewish kindred from Iran using a DNA pooling strategy which takes advantage of the likelihood that the disease is inherited by all affected individuals from a common founder.

Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis.

Evidence is reviewed suggesting that the free opsin present during vitamin A deprivation or the mutated Opsin present in some forms of RP excite the visual transduction cascade, which would produce a constant 'equivalent light' that triggers photoreceptor degeneration.

Cloning, Chromosomal Localization and Functional Expression of the Gene Encoding the α‐Subunit of the cG‐MP‐Gated Channel in Human Cone Photoreceptors

The cloning of the cDNA encoding the α‐subunit of the CNG channel of human cone photoreceptors, located on the pericentric band q11.2 of human chromosome 2, is reported here.

Rod and cone photoreceptor cells express distinct genes for cGMP-gated channels