CNGB1 – Retinitis Pigmentosa

Cyclic nucleotide-gated channel β1 (CNGB1) encodes the β subunit of the rod photoreceptor cyclic nucleotide-gated channel. Biallelic loss-of-function and missense variants in CNGB1 cause autosomal recessive retinitis pigmentosa, presenting with early nyctalopia, midperipheral visual field constriction and progressive rod-cone dystrophy.

Inheritance is autosomal recessive with over 150 unique CNGB1 variants reported in more than 200 unrelated probands, including 24 missense, 21 nonsense, 19 canonical and noncanonical splice, 10 small deletions, and 7 duplications (PMID:33847019). A case series of 10 patients from 9 families confirmed the pathogenicity of novel nonsense (p.Gln88Ter, p.Gln222Ter, p.Gln318Ter, p.Arg729Ter), frameshift (p.Leu849AlafsTer3, p.Ala1048fsTer13), and splice site (c.761+5G>C) variants (NM_001297.5:c.2544dup (p.Leu849AlafsTer3)) with preserved central acuity but characteristic rod-cone dysfunction (PMID:28056120).

Segregation data include a consanguineous Han Chinese family with a homozygous frameshift c.385delC (p.Leu129TrpfsTer148) confirmed in proband and heterozygous in an unaffected son (PMID:30451805), and a sibship of six in which compound heterozygous missense c.2603G>A (p.Gly868Asp) and in-frame duplication c.2093_2104dup (p.Cys698_Ile701dup) segregated with disease in four affected siblings (PMID:32613137). In total, at least 3 additional affected relatives demonstrate variant segregation.

Mechanistically, CNGB1 truncating variants disrupt channel assembly and rod outer segment targeting of CNGA1, leading to primary rod photoreceptor degeneration. In a Papillon dog model, a complex exon 26 frameshift (c.2387delA;2389_2390insAGCTAC) abolished CNGB1 and secondary CNGA1 localization in rods, recapitulating human PRA (PMID:23977260).

Gene augmentation therapy using rAAV5.hCNGB1 under a human rhodopsin promoter in Cngb1 knockout mice yielded dose-dependent recovery of rod-driven responses, normalization of CNGA1 expression, and preservation of photoreceptor morphology, supporting a wide therapeutic window (PMID:29202463).

Collectively, robust genetic, segregation, and concordant functional data establish a definitive association between CNGB1 and autosomal recessive retinitis pigmentosa. The preservation of central vision into adulthood and successful preclinical gene therapy highlight CNGB1-RP as an ideal target for clinical intervention.

References

• Human Mutation • 2021 • CNGB1-related rod-cone dystrophy: A mutation review and update PMID:33847019
• JAMA Ophthalmology • 2017 • Clinical Characterization of CNGB1-Related Autosomal Recessive Retinitis Pigmentosa PMID:28056120
• PLoS One • 2013 • A large animal model for CNGB1 autosomal recessive retinitis pigmentosa PMID:23977260
• The Journal of Clinical Investigation • 2018 • Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach PMID:29202463

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