Gnat1-KO Mouse

GNAT1, encoding the rod-specific transducin α-subunit, is a key element in the rod phototransduction cascade [2,3]. Phototransduction is the process by which light is converted into electrical signals in the retina, crucial for vision. Mutations in GNAT1 are associated with congenital stationary night blindness (CSNB) and other retinal disorders, highlighting its importance in maintaining normal visual function [1,2,3]. Genetic models, such as gene knockout mice, have been valuable in studying its function.

In a consanguineous Pakistani family, a missense mutation in GNAT1 (p.D129G) was associated with autosomal recessive stationary night blindness [2]. A Japanese family with Nougaret-type CSNB and cone-rod dystrophy (CORD) had a GNAT1 variant (p.G38D), and co-existence of GNAT1 and biallelic ABCA4 variants was associated with an overlapping phenotype of CSNB and CORD [1]. A novel homozygous truncating mutation in GNAT1 was found in a patient with retinitis pigmentosa, indicating it can cause late-onset retinal degeneration [3]. In Gnat1-/-mice, constitutively depolarized rods release excessive glutamate, accelerating deep plexus angiogenesis and paracellular blood-retinal barrier maturation [4]. Also, in Gnat1-/ -; Gnat2cpfl3/cpfl3 double-knockout mice, which lack rod and cone α-transducin proteins, melanopsin-mediated phototransduction could still contribute to the primary pattern-forming visual pathway [5].

In conclusion, GNAT1 is essential for normal rod-mediated phototransduction. Studies using gene knockout mouse models have revealed its role in various retinal diseases such as CSNB, CORD, and retinitis pigmentosa. These models have provided insights into how GNAT1 mutations can disrupt normal visual function and associated biological processes in the retina.

References:

1. Hayashi, Takaaki, Hosono, Katsuhiro, Kurata, Kentaro, Nakano, Tadashi, Hotta, Yoshihiro. 2019. Coexistence of GNAT1 and ABCA4 variants associated with Nougaret-type congenital stationary night blindness and childhood-onset cone-rod dystrophy. In Documenta ophthalmologica. Advances in ophthalmology, 140, 147-157. doi:10.1007/s10633-019-09727-1. https://pubmed.ncbi.nlm.nih.gov/31583501/

2. Naeem, Muhammad Asif, Chavali, Venkata R M, Ali, Shahbaz, Hejtmancik, J Fielding, Riazuddin, S Amer. 2012. GNAT1 associated with autosomal recessive congenital stationary night blindness. In Investigative ophthalmology & visual science, 53, 1353-61. doi:10.1167/iovs.11-8026. https://pubmed.ncbi.nlm.nih.gov/22190596/

3. Carrigan, Matthew, Duignan, Emma, Humphries, Pete, Kenna, Paul F, Farrar, G Jane. 2015. A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration. In The British journal of ophthalmology, 100, 495-500. doi:10.1136/bjophthalmol-2015-306939. https://pubmed.ncbi.nlm.nih.gov/26472407/

4. Biswas, Saptarshi, Shahriar, Sanjid, Bachay, Galina, Brunken, William J, Agalliu, Dritan. 2024. Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/β-catenin signaling. In Neuron, 112, 1978-1996.e6. doi:10.1016/j.neuron.2024.03.011. https://pubmed.ncbi.nlm.nih.gov/38599212/

5. Flood, Michael D, Veloz, Hannah L B, Hattar, Samer, Carvalho-de-Souza, Joao L. 2022. Robust visual cortex evoked potentials (VEP) in Gnat1 and Gnat2 knockout mice. In Frontiers in cellular neuroscience, 16, 1090037. doi:10.3389/fncel.2022.1090037. https://pubmed.ncbi.nlm.nih.gov/36605613/