Department of Molecular Medicine

University of Texas Health Science Center at San Antonio

San Antonio, Texas

BASIC RESEARCH PROJECT

Novel human Oguichi disease mechanisms

Research Interests

Oguchi disease is an autosomal recessive disorder disabling the arrestin (Arr1)2
and the rhodopsin kinase (Grk1) genes which are required for timely deactivation of visual pigments in rod and cone photoreceptors. Reported first by Dr. Chuta Oguchi in 1907, affected individuals are night blind with a diagnostic shiny metallic fundus appearance that turns normal following prolonged dark adaptation, aka the Mizuo-Nakamura phenomenon. Dr. Chen’s laboratory modeled this disease in the 90s in the Grk1-/- mice and reported a previously unknown light-dependent rod degeneration phenotype5, which was later confirmed and found in human patients.

Plans for 2024

This project is built on Dr. Chen’s experience with the Grk1 gene5 and the not fully understood rhodopsin kinase (GRK1) it encodes to systematically investigate thirteen disease-causing missense mutations found in this gene with the hope to gain insights on its activation mechanism, as well as settling a long-standing mystery concerning the mechanism of reproducibility of rod’s single photon response (SPR).

Dr. Chen hypothesizes that some Grk1 missense mutations hamper the activation of GRK1 and reduce its ability to compete with transducin resulting in enlarged and varied rod SPR.

In 2024, his laboratory will establish that there are more disease-causing mechanisms than the one and only contemporary view of catalytic incapability for Oguchi disease.

The information to be obtained here will significantly impact the genetically heterogeneous retinitis pigmentosa (RP) field where the rhodopsin gene, GRK1’s sole substrate, harbors the most disease-causing mutations. There is no cure yet for rhodopsin-associated RP due to insufficient basic information concerning how it is deactivated and when not, how prolonged rhodopsin signaling kills rod cells. The proposed study will thus provide the missing piece of information toward a full understanding of GRK1’s activation process, an indispensable step toward developing new therapeutic modalities to treat rhodopsin-related and other hereditary human blinding diseases.