Achromatopsia

Achromatcpsia (syn. Total Colorblindness or Rodmonochromacy) is an autosomal recessive congenital and stationary ocular disorder with a prevalence of 1 in 30,000 (Francois et at. ). Clinically it is characterized by severe photophobia under daylight conditions and nystagmus, both symptoms become evident within the first months after birth. Visual acuity is strongly reduced to less than 0.2 and color discrimination is strongly impaired or impossible. In ERG (electroretinography) recordings, rod function is normal, but cone function is absent or strongly reduced

In the past years, two loci for complete achromatopsia, ACHM2 (MIM216900) and ACHM3 (MIM2623O0), have been assigned by linkage analysis to chromosome 2q11 and 8q21, respectively (Arbour et al. 1997; Wissinger et al, 1998; Kohl et al, 2000). Subsequently, mutations in the CNGA3 (MlM60O053) and the CNGB3 genes (MlM6O5O8O) were shown to segregate with the ACHM2 (Kohl et al. 1998) and the ACHM3 locus (Kohl et al, 2000; Sundin et al. 2000), respectively, in families with complete achromatopsia. Mutations in the CNGA3 gene account for approximately 2O-3O%, and mutations in the CNGB3 gene for 40-50% of all achromatopsia patients (Wissinger et at. 2001; Kohl et al 2005). This clearly shows that the ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia. However, these results also provide evidence for further genetic heterogeneity in this rare disorder. Recently, mutations in the GNAT2 gene (MIM13934O) on chromosome 1p13 were shown to account for a small percentage (near 2%) of this rare disorder (Kohl et al. 2002). GNAT2 encodes the cone-specific alpha-subunit of transducin, a heterotrimeric G-protein that couples to the cone visual pigments. Excited pigment molecules induce the exchange of GDP to GTP at the guanosine binding site of the transducin alpha-subunit and its subsequent release from the inhibitory beta-/gamma-subunits. The activated GTP - transducin then binds ant activates a phosphodiesterase that hydrolyses cGMP and effectively reduces its intercellular concentration. This results in closure of the cGMp-gated channels and subsequently in membrane hyperpolarization. CNGA3 and CNGB3 encode the channel-forming alpha- and putative modulatory beta-subunits of the heterotetrameric cone photoreceptor cGMP-gated (CNG) channel, respectively. Transducin thus mediates one of the first steps of the phototransduction cascade, while the cGMP-gated channel represents the final component of the very same pathway. Considering the importance of transducin and the CNG channel in phototransduction, the phenotype of achromatopsia can easily be explained by mutations in the GNAT2, the CNAG3 or the CNGB3 gene. Furthermore, it implies that the same transducin alpha-subunit and the same CNG channel is common to all three types of cone photoreceptors.