Unexpected cause of inherited color blindness identified

In the last 15 years, Susanne Kohl and Bernd Wissinger, together with their colleagues at the Institute for Ophthalmic Research, have already identified five genes (CNGA3, CNGB3, GNAT2, PDE6C and PDE6H) that can cause this rare disease. All these previously identified genes encode for proteins essential for phototransduction in cone photoreceptors. Thus, the association of the genetic defect with the visual disorder was self-evident.

Identifying the genetic cause of a disease is important, but do patients profit from such a discovery? - „One should not underestimate the importance of knowing the exact cause of an inherited disease to a patient and their families.“ Prof. Wissinger emphasizes,  "It is the final step to confirm a clinical diagnosis for in inherited disease. In addition, this knowledge enables exact genetic counseling within a family and may be the first step to develop new therapeutic approaches“.

The new gene that was now identified – ATF6 – does not fit into this scheme: ATF6 is expressed in every cell of the human body, and is known to acts as a sensor for ER stress, i.e. the accumulation of misfolded protein in the endoplasmatic reticulum. ATF6 is capable to sense this insult and trigger one of three known signaling pathways that counteract ER stress (i.e. to drive Unfolded Protein Response). This was state-of-knowledge thus far. The finding that a genetic defect in ATF6 results in an ocular only disorder like Achromatopsia, hereby exclusively affecting cone photoreceptors, is absolutely unexpected and surprising.

The Tübingen group profited from in-house expertise (Prof. Zrenners group: Clinical characterization of patients and Prof. Seeligers group: In vivo characterization of mouse models) and intense long-term collaborations with numerous clinical experts in the field of inherited retinal disease throughout Europe and North America. In addition, a productive cooperation with the groups of Jonathan Lin (UCSD) and Randal Kaufman (Sanford Burnham), both of them experts on ER stress and ATF6 biology, was established.

„Genetic defects and mutations in ATF6 account for only a small proportion of Achromatopsia patients, but they provide evidence for a complete new and unexpected disease mechanism underlying this rare cone photoreceptor disorder“, Susanne Kohl explains the importance of their results. An article describing these findings is currently published in the renowned journal „Nature Genetics“, a world-leading scientific journal for genetic studies.