CNGB3 – Cone Dystrophy

CNGB3 encodes the β‐subunit of the cone photoreceptor cyclic nucleotide‐gated channel. Autosomal recessive variants in CNGB3 have been implicated in progressive cone dystrophy, manifesting as early-onset visual acuity loss, photophobia, and color vision defects.

In a longitudinal multicenter cohort (N = 98 CD probands, 41 affected relatives), direct sequencing identified CNGB3 mutations in 3 of 90 autosomal recessive cone dystrophy cases, with segregation in affected kindreds (3 probands, 41 relatives) ([PMID:22264887]).

A consanguineous Indian family with three of six siblings affected by cone dystrophy harbored a homozygous frameshift variant c.1148del (p.Thr383fs), which co-segregated with disease and truncates the B3 subunit ([PMID:28746191]).

The CNGB3 c.1208G>A (p.Arg403Gln) allele was identified in 16 unrelated individuals presenting a spectrum from achromatopsia to progressive cone dystrophy. A triallelic mouse model combining Cngb3R403Q/R403Q with heterozygous Cnga3 loss recapitulated and exacerbated cone dysfunction, confirming a digenic triallelic mechanism ([PMID:30418171]).

Functional studies of disease-associated CNGB3 variants (e.g., p.Arg403Gln, p.Phe525Asn, p.Thr383fs) in Xenopus oocytes and photoreceptor-derived cells demonstrated gain-of-function channel alterations, increased ligand sensitivity, and calcium-dependent cytotoxicity, linking channelopathy to photoreceptor degeneration ([PMID:16379026], [PMID:23805033]).

Collectively, autosomal recessive inheritance, segregation across multiple families, in vivo mouse models, and in vitro functional assays provide strong evidence that CNGB3 variants cause cone dystrophy via channel dysfunction and photoreceptor toxicity. Key take-home: CNGB3 genetic testing informs diagnosis, prognosis, and potential eligibility for emerging gene therapies in cone dystrophy.

References

• Ophthalmology • 2012 • Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. PMID:22264887
• Medicine • 2017 • Whole exome sequencing unveils a frameshift mutation in CNGB3 for cone dystrophy: A case report of an Indian family. PMID:28746191
• The Journal of Clinical Investigation • 2018 • Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. PMID:30418171
• Molecular Vision • 2005 • Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels. PMID:16379026
• Molecular Vision • 2013 • Disease-associated mutations in CNGB3 promote cytotoxicity in photoreceptor-derived cells. PMID:23805033

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