Improper targeting of membrane proteins causes many diseases. Often point mutations to cysteine hinder the delivery of membrane proteins to the cell surface 
, or to the correct side of polarized cells 
. Because cysteine is a readily reactive amino acid, in principle it should be possible to recover proper trafficking by modifying its chemical structure in order to mimic the side chain of the wild type amino acid. As a proof of principle, we have studied two naturally occurring cysteine mutations in a cyclic nucleotide-gated channel (CNGA3) responsible for hereditary cone photoreceptor disorders: Y181C linked to incomplete achromatopsia and R277C linked to complete and incomplete achromatopsia or cone dystrophy 
. We have chosen these mutations because proper surface CNG channel expression can be easily assayed using electrophysiological techniques, and because both mutations, which cause channel retention in the endoplasmic reticulum (ER) 
, change wild type amino acids of drastically different chemistries.
CNG channels open a cationic selective permeation pathway in response to intracellular cyclic nucleotides 
. In the visual system, CNG channels are key players in the transduction of light into electrical signals 
. In native cells, these channels are formed by the coassembly of four homologous subunits 
, each containing six transmembrane segments. Functional homotetramers can be formed by the CNGA1, A2 or A3 subunits 
, and these channels are usually studied as homotetramers in heterologous systems. We have introduced both achromatopsia-related cysteines in a cysteine-less CNGA1 channel 
, and used them as a target for specific chemical modification with hydroxybenzyl- (MTSHB) and aminoethyl-methanethiosulfonate (MTSEA). These reagents readily attach to the side chain of cysteines and mimic the chemistry of tyrosine and arginine, respectively (). Although Y181C and R277C caused ER retention, after chemical modification both mutants were targeted to the cell surface, providing a unique opportunity for their functional characterization.