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GNAT2 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: G protein subunit alpha transducin 2
  • Expressed in cones and involved in the cone phototransduction cascade
  • Light-activated opsins interact with transducin, which in turn activates cyclic guanosine monophosphate (cGMP)-phosphodiesterase
  • Activated cGMP-phosphodiesterase closes the cGMP-gated ion channels which in turn causes hyperpolarisation of the photoreceptor plasma membrane
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • Autosomal recessive
Ocular features
  • Nystagmus from birth/early infancy
  • Photophobia
  • Normal appearing fundus is common but some may display macular RPE mottling
  • Adaptive optics scanning light ophthalmoscopy shows relatively well-preserved cone mosaic compared to other causative genes of achromatopsia
Visual function
  • Complete and incomplete achromats with GNAT2 variants have been reported
  • Visual impairment evident from birth/early infancy
  • Variable severity of colour vision impairment and reduced visual acuity
  • Affected individuals may be seen to favour dimly-lit environment
Systemic features
  • No specific extraocular features
Key investigations
  • Full-field ERG (ffERG): Severely reduced cone response with normal/subnormal rod response
  • FAF: Usually appears normal
  • OCT: Usually normal appearing with a continuous EZ; some may display a hyporeflective zone at the fovea
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
Therapies under research
Further information

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Multimodal imaging

Different images of the retina of a patient with achromatopsia due to mutations in the GNAT2 gene. No abnormalities in the retina was found in all imaging protocols.
Multimodal imaging of a patient with GNAT2-achromatopsia. Both wide field colour fundus photograph (A) and FAF imaging (B) are unremarkable. The OCT scan of the macula (C) looks normal.

References

  1.  Morris T, Fong S. Characterization of the Gene Encoding Human Cone Transducin α-Subunit (GNAT2). Genomics. 1993;17(2):442-448
  2.  Müller F, Kaupp U. Signaltransduktion in Sehzellen. Naturwissenschaften. 1998;85(2):49-61
  3.  Kohl S, Baumann B, Rosenberg T et al. Mutations in the Cone Photoreceptor G-Protein α-Subunit Gene GNAT2 in Patients with Achromatopsia. The American Journal of Human Genetics. 2002;71(2):422-425
  4.  Kohl S, Marx T, Giddings I et al. Total colourblindness is caused by mutations in the gene encoding the α-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet. 1998;19(3):257-259
  5.  Sundaram V, Wilde C, Aboshiha J, Cowing J, Han C, Langlo C. Retinal structure and function in achromatopsia: implications for gene therapy. Ophthalmology. 2014;121:234–45
  6.  Michaelides M, Aligianis IA, Holder GE, et al. Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2) [published correction appears in Br J Ophthalmol. 2004 Feb;88(2):314]. Br J Ophthalmol. 2003;87(11):1317-1320
  7.  Bidaut Garnier M, Flores M, Debellemanière G et al. Reliability of cone counts using an adaptive optics retinal camera. Clin Exp Ophthalmol. 2014;42(9):833-840
  8.  Felden J, Baumann B, Ali M, et al. Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene. Hum Mutat. 2019;40(8):1145-1155
  9.  Georgiou M, Singh N, Kane T, et al. Photoreceptor Structure in GNAT2-Associated Achromatopsia. Invest Ophthalmol Vis Sci. 2020;61(3):40

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Updated on November 30, 2020
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