PDE6B – Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive rod–cone degeneration and night blindness. The PDE6B gene (HGNC:8786) encodes the beta subunit of rod-specific cGMP phosphodiesterase, a key effector in phototransduction. Biallelic PDE6B variants cause autosomal recessive RP, with onset typically in childhood and variable severity identified across diverse populations. Functional studies and animal models have long supported this gene–disease relationship, establishing a definitive association.

PDE6B-related RP follows autosomal recessive inheritance, with multiple consanguineous and outbred pedigrees showing co-segregation of pathogenic alleles. Segregation analyses in a consanguineous Israeli family with three affected siblings and in a Pakistani pedigree with two affected siblings confirmed homozygosity for severe LoF alleles ([PMID:23882135]; [PMID:36959549]). Recurrent loss-of-function variants—nonsense, frameshift, and canonical splice site changes—predominate, although hypomorphic and missense alleles also contribute to disease.

In a multicenter cohort of 24 patients from 21 families, 23 distinct PDE6B variants were identified: eight predicted to disrupt splicing and seven missense changes, with symmetrical visual function metrics supporting uniform rod dysfunction ([PMID:33673512]). A founder intronic splice-site mutation, c.1921-9C>G (p.Thr641_Lys642ins8), accounts for ~40% of PDE6B-RP in Caucasus Jews and demonstrates a clear linkage disequilibrium signature ([PMID:30820151]).

Case reports further expand the mutational spectrum: a homozygous insertion–deletion, c.1923_1969ins6del47 (p.Cys641Ter), segregated with rod–cone degeneration and cystoid macular edema in an American pedigree ([PMID:24828262]). A consanguineous Pakistani family harbored a novel missense change, c.938T>A (p.Thr313Ile), co-segregating with early-onset night blindness and retinal thinning ([PMID:36959549]).

Animal models provide concordant evidence: null rd1 mice lacking PDE6B exhibit rapid photoreceptor loss by postnatal week 3, while hypomorphic Pde6b(H620Q) mutants show slower degeneration yet recapitulate human RP histopathology ([PMID:16123450]). Gene therapy via lentiviral Pde6b delivery rescues photoreceptor structure and function in hypomorphic mice, underscoring haploinsufficiency as the pathogenic mechanism ([PMID:18658088]).

Overall, over 30 probands across >20 years and multiple independent studies firmly establish a definitive gene–disease relationship for PDE6B and RP. The consistent AR inheritance, robust segregation, and concordant animal and rescue data support both diagnostic genetic testing and therapeutic targeting. Key take-home: PDE6B variants produce a clinically recognizable, autosomal recessive RP with well-validated functional mechanisms and outcome measures amenable to future gene therapies.

References

• Genomics • 1995 • Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa PMID:8595886
• Current Eye Research • 1998 • A novel homozygous Ile535Asn mutation in the rod cGMP phosphodiesterase beta-subunit gene in two brothers of a Japanese family with autosomal recessive retinitis pigmentosa PMID:9543643
• Molecular Vision • 2013 • Genetic heterogeneity and consanguinity lead to a "double hit": homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa PMID:23882135
• Ophthalmic Genetics • 2014 • Next-generation sequencing revealed a novel mutation in the gene encoding the beta subunit of rod phosphodiesterase PMID:24828262
• International Journal of Molecular Sciences • 2021 • Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa PMID:33673512
• Molecular Vision • 2019 • A novel intronic mutation of PDE6B is a major cause of autosomal recessive retinitis pigmentosa among Caucasus Jews PMID:30820151
• Investigative Ophthalmology & Visual Science • 2005 • Genotype-phenotype correlation of mouse pde6b mutations PMID:16123450
• Investigative Ophthalmology & Visual Science • 2008 • Functional rescue of degenerating photoreceptors in mice homozygous for a hypomorphic cGMP phosphodiesterase 6 b allele (Pde6bH620Q) PMID:18658088

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