GNAT2

GNAT2 is a gene that encodes the cone transducin alpha subunit (Gαt2), a member of the G protein alpha subunit family. The protein is expressed in cone photoreceptors of the retina and plays a key role in the vertebrate visual phototransduction cascade. As part of the cone transducin heterotrimer, Gαt2 participates in the signal transduction that converts light into electrical signals in cone cells.

In darkness, Gαt2 participates in a heterotrimer with Gβ and Gγ subunits and remains in an inactive GDP-bound state. Upon photon absorption by cone opsins, the opsin catalyst promotes GDP to GTP exchange on Gαt2, activating it. Active Gαt2 then stimulates the cGMP phosphodiesterase PDE6C, reducing intracellular cGMP levels. This leads to closure of cyclic nucleotide-gated channels, hyperpolarization of the cone photoreceptor, and modulation of neurotransmitter release to downstream neurons.

GNAT2 expression is cone-specific in the retina, with high conservation across vertebrates. The protein contains conserved GTPase and effector-interaction domains characteristic of GNAT family members, enabling it to interact with PDE6C and other components of the phototransduction machinery.

Clinical significance is mainly seen in inherited cone dysfunction disorders. Pathogenic variants in GNAT2 are associated with autosomal recessive achromatopsia, a condition characterized by severely reduced or absent cone function, color vision deficiency, photophobia, nystagmus, and decreased visual acuity. Genetic testing can identify biallelic GNAT2 variants in affected individuals, aiding diagnosis and genetic counseling. In addition to achromatopsia, GNAT2 mutations can contribute to cone dystrophy phenotypes with progressive cone degeneration.

Research uses GNAT2-related models to study cone signaling and potential therapies for cone-mediated vision loss.