CNGB3 Membrane Protein Introduction

Introduction of CNGB3

CNGB3 is encoded by the CNGB3 gene and is also known as Cyclic nucleotide-gated cation channel beta-3, Cone photoreceptor cGMP-gated channel subunit beta, Cyclic nucleotide-gated cation channel modulatory subunit, Cyclic nucleotide-gated channel beta-3 and CNG channel beta-3. It belongs to the cone cyclic nucleotide-gated (CNG) channel, which is essential for central and color vision and visual acuity. This channel is composed of two structurally related subunits, CNGA3 and CNGB3; CNGA3 is the ion-conducting subunit, whereas CNGB3 is a modulatory subunit. Meanwhile, the structural modeling of CNGB3 suggests that CNGB3 possesses six trans-membrane helixes.

Function of CNGB3 Membrane Protein

Cyclic nucleotide-gated (CNG) channels are composed of two structurally related subunit types, the A and B subunits. The rod channel consists of CNGA1 and CNGB1 subunits, whereas the cone channel contains CNGA3 and CNGB3 subunits. CNG channels are localized to the plasma membrane of photoreceptor outer segments (OS) and play a pivotal role in phototransduction. Mutations in the rod CNG channel have been identified in patients with retinitis pigmentosa, whereas mutations in the cone CNG channel are associated with achromatopsia, progressive cone dystrophy and early-onset macular degeneration. To date, more than 70 mutations have been identified in the human CNGA3 and CNGB3 genes, and mutations in CNGB3 are found in 50% of achromatopsia patients. CNGB3 is a modulatory subunit of the cone CNG channel. Although CNGB3 shares a common topology with CNGA3 and possesses a pore-forming region, expression of CNGB3 alone does not form a functional channel, CNGA3/CNGB3 heteromeric channels display a number of properties typical of native CNG channels.

Fig.1 Predicted crystal structures of CNGB3 protein (Li F-F, 2015)

Application of CNGB3 Membrane Protein in Literature

1. Ding X., et al. Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism. Human molecular genetics. 2009, 18 24 (2009): 4770-80. PubMed ID: 19767295
   
   

   This article reports that the loss of CNGB3 reduces the biosynthesis of CNGA3 and impairs cone CNG channel function. They suggest that down-regulation of CNGA3 contributes to the pathogenic mechanism by which CNGB3 mutations lead to human cone disease.

2. Carvalho L.S., et al. Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Hum. Mol. Genet. 2011, 20(16):3161-3175. PubMed ID: 21576125
   
   

   This article reveals that the phenotype of CNGB3^−/− mice reflects the symptoms of patients carrying CNGB3 mutations, namely impaired cone function and early onset, slow progression of cone degeneration. More importantly, the authors in this article try to use this novel model of CNGB3 deficiency to optimize treatment for the most common form of achromatopsia.

3. Khan N.W., et al. CNGB3 Achromatopsia with Progressive Loss of Residual Cone Function and Impaired Rod-Mediated Function. Investigative Ophthalmology & Visual Science. 2007, 48(8):3864-3871. PubMed ID: 17652762
   
   

   Authors in this group characterize the clinical physiology of photoreceptor function in two families with two CNGB3 genotypes and report several novel features for this form of achromatopsia. Meanwhile, although the CNGB3 protein subunit is known to be expressed only in cone photoreceptors, some affected individuals demonstrated rod functional abnormalities to various degrees.

4. Bright S. R., et al. Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels. Molecular vision 11. 2005, 1141-50. PubMed ID: 16379026
   
   

   This article focuses on the gating effects of two previously uncharacterized disease-associated mutations in the CNGB3 subunit and found that in each case, the mutations resulted in a gain of function molecular phenotype. Furthermore, the magnitude of the effect on channel function correlated with the severity of the associated disease.

5. Kohl S., et al. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Europ. J. Hum. Genet. 2004, 13:302. PubMed ID: 15657609
   
   

   This article evaluates the mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia, indicating that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.

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Reference

1. Li F-F., et al. (2015) Identification of novel mutations by targeted exome sequencing and the genotype-phenotype assessment of patients with achromatopsia. Journal of Translational Medicine. 13(1):334.

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