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Mutation leading to RP identified

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A single mutation within the rhodopsin gene causes a domino effect, eventually leading to retinitis pigmentosa, according to a study published in the Journal of Biological Chemistry. Understanding the cascade may allow for the creation of drugs designed to stabilize the protein, the authors wrote.

Using compensatory mutations in conjunction with crystal structure-based molecular analysis, John Hwa, MD, PhD, and colleagues with Dartmouth Medical School determined that the positively charged Arg replaces Leu125, sterically hindering the adjacent Trp126. It also disrupts an interhelical interaction between transmembrane III and transmembrane V, which is known as the Glu122-His211 salt bridge.

According to the study, Val also interferes with Leu119 and Ile123 on transmembrane III, leading to disruption of the same Glu122-His211 salt bridge.

The authors wrote that these localized defects combined cause structural changes that interfere opsin's ability to bind 11-cis-retinal, ultimately leading to an abnormal disulfide bond, severe protein instability, aggregation and endoplasmic reticulum retention.