Human Cyclic Nucleotide Gated Channel Beta 1 (CNGB1) is located on chromosome 16 at cytogenetic location 16q21. The gene consists of 12 exons spanning approximately 11 kb. CNGB1 codes for one subunit of a rod photoreceptor cGMP-gated cation channel that in humans helps regulate ion flow into photoreceptors of the eye in response to changes in intracellular cGMP in response to light. CNGB1 gene defects cause a type of blindness called retinitis pigmentosa type 45.
CNGB1 is also known as CNG4, GAR1, GARP, RP45, CNCG2, CNCG4, GARP2, RCNC2, RCNCb, CNCG3L, CNGB1a, CNGB1b and RCNCbeta. CNGB1 splice variants GARP1 and GARP2 are expressed in the retina. Splice variant CNGB1b is expressed in the olfactory sensory neurons and other tissues. CNGB1a and CNGB1b are are components of CNG channels.
Genes homologous to human CNGB1 exist in mouse and dog, animals which also serve as models for RP45. Putative homologs of human CNGB1 have also been found in chimpanzee (Pan troglodytes), rhesus macaque (Macaca mulatta), wolf (Canis lupus), domestic cow (Bos Taurus), brown rat (Rattus norvegicus), chicken (Gallus gallus) and nematode (Caenorhabditis elegans).
cGMP stands for cyclic guanosine monophosphate (cGMP) which is a cyclic nucleotide derived from guanosine triphosphate (GTP). Cyclic nucleotide-gated (CNG) ion channels are activated by binding cGMP or cAMP (cyclic adenosine monophosphate). Changes in intracellular concentrations of cyclic nucleotides are transduced into changes in membrane potential and calcium ion (Ca2+) concentration. In the retinal rod photoreceptor cGMP-gated cation channel, the CNGB1 gene codes for the beta subunit and the CNGA1 gene codes for the alpha subunit.
CNG channels in rod receptors are composed of three CNGA1 subunits and one CNGB1 (CNGB1a) subunit. The CNGB1b subunit combines with two CNGA2 subunits and one CNGA4 subunit in CNGs of olfactory receptors. CNGA1 can form functional channels on their own but CNGB1 subunits do not. CNGB1 subunits provide enhanced Ca2+ permeation, modulation by Ca2+-calmodulin and affect nucleotide specificity compared to channels composed of only homomeric CNGA.
GARP2 (glutamic acid-rich protein 2) is an alternate isoform formed by alternative splicing of the CNGB1 transcribed RNA. GARP2 is a high affinity rod photoreceptor phosphodiesterase (PDE6)-binding protein that regulates spontaneous activation of rod PDE6, lowering ‘dark nose’ and enabling photoreceptors to function at the single photon detection limit. PDE6 are the sixth family of phosphodiesterases of cyclic nucleotides (PDEs). They are photoreceptor-specific PDEs serving as effector enzymes in vertebrate phototransduction.
In olfactory receptor neurons CNG channels generate a receptor current in response to an odorant-induced rise in cAMP. This channel is comprised of CNGA2 which is the principal subunit plus two modulatory subunits, CNGA4 and CNGB1b. CNGB1 -/- deficient mice show decreased olfactory performance and electro-olfactogram responses show a reduced amplitude and decelerated onset and recovery kinetics compared with wild-type mice. Electrophysiological recordings showed that CNG current was weakly expressed in the olfactory receptor neurons, with decreased cAMP sensitivity in CNGB1 deficient mice. Without CNGB1, the olfactory CNG channel did not target to the olfactory cilia. A small study suggests olfactory function is compromised in people with CNGB1 mutations on both alleles.
Retinitis pigmentosa is a heterogeneous group of inherited ocular diseases characterized by progressive retinal degeneration, causing constriction of visual fields and night blindness, affecting 1 in 3000 to 5000 people. Patients with RP45 typically have night blindness from childhood and loss of peripheral vision has a later onset with RP diagnosis at around 30 years of age and legal blindness around about 60 years of age. RP45 are caused by mutations in CNGB1 which are responsible for approximately 4% of autosomal recessive RP.
Retinitis pigmentosa 45 (RP45) was discovered by Bareil et al. (2001) in a consanguineous French family who showed that autosomal recessive segregation of the trait was caused by a missense mutation in exon 30 of the CNGB1 gene. Kondo et al. (2004) identified a homozygous splice site mutation in the CNGB1 gene that resulted in a frameshift and truncation of the protein. A homozygous missense mutation at a conserved residue in the CNGB1 gene was found to segregate with the disease in a Chinese family by Fu et al. (2013).
Amino acid changes for missense mutations:
- c.385delC, p.(L129WfsTer148)
Splice site mutations:
- c.3444+G>A resulting in a frameshift and skipping exon 32 and truncation of the protein
Cngb1-X26 is a mouse model missing the full-length protein which was generated by excision of exon 26. The mice show significantly decreased rod function and retinal degeneration. Gene therapy with adeno-associated viral (AAV) vectors carrying CNGB1a cDNA with a rod-specific promoter resulted in restoration of vision and delay in retinal degeneration in these CNGB1 knockout mice.
A frameshift mutation in CNGB1 causing canine progressive retinal atrophy, a condition resembling retinitis pigmentosa, was found in the Papillon dog breed by two research groups and also in the Phalene dog breed. The first test for the canine mutation was licensed to OptiGen by the research team lead by Simon Petersen-Jones that discovered the CNGB1 mutation in papillon dogs. Gene therapy introducing a normal copy of canine Cngb1a into rod photoreceptors resulted in restoration of rod function and preserved retinal structure in Cngb1-/- dogs.
Invest Ophthalmol Vis Sci. 2013 Jun 14;54(6):4158-66. doi: 10.1167/iovs.13-11672.
Next-generation sequencing-based molecular diagnosis of a Chinese patient cohort with autosomal recessive retinitis pigmentosa.
Fu Q1, Wang F, Wang H, Xu F, Zaneveld JE, Ren H, Keser V, Lopez I, Tuan HF, Salvo JS, Wang X, Zhao L, Wang K, Li Y, Koenekoop RK, Chen R, Sui R.
Department of Ophthalmology, North Huashan Hospital, Fudan University, Shanghai, China.
Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4433-9.
A homozygosity-based search for mutations in patients with autosomal recessive retinitis pigmentosa, using microsatellite markers.
Kondo H1, Qin M, Mizota A, Kondo M, Hayashi H, Hayashi K, Oshima K, Tahira T, Hayashi K.
Department of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan.
Neuron. 2002 Dec 5;36(5):891-6.
Zheng J1, Trudeau MC, Zagotta WN.
Howard Hughes Medical Institute, Seattle, WA 98195, USA.
Hum Genet. 2001 Apr;108(4):328-34.
Bareil C1, Hamel CP, Delague V, Arnaud B, Demaille J, Claustres M.
Laboratoire de Génétique Moléculaire, IURC, and CNRS UPR 1142, Montpellier, France.
Genomics. 1995 Jul 1;28(1):32-8.
Ardell MD1, Makhija AK, Oliveira L, Miniou P, Viegas-Péquignot E, Pittler SJ.
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile 36688-0002, USA.
Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11757-61.
Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.
Chen TY1, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3116-9.
The amino acid sequence of a glutamic acid-rich protein from bovine retina as deduced from the cDNA sequence.
Sugimoto Y1, Yatsunami K, Tsujimoto M, Khorana HG, Ichikawa A.
Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.