GPR179 – Congenital Stationary Night Blindness

Congenital stationary night blindness (CSNB) is an inherited retinal disorder marked by non-progressive rod–bipolar signal transmission defects. GPR179 encodes a G protein-coupled receptor localized to ON-bipolar cell dendritic tips. Multiple independent cohorts have identified biallelic GPR179 variants in patients with the complete form of CSNB, demonstrating a consistent autosomal recessive inheritance pattern and loss-of-function mechanism.

In a whole-exome sequencing study of CSNB patients lacking known gene defects, a homozygous missense variant, c.1807C>T (p.His603Tyr) (PMID:22325361), was discovered in a consanguineous pedigree, and a frameshift, c.278delC (p.Pro93GlnfsTer57), in a simplex case. Screening of 40 additional CSNB probands identified three more individuals with GPR179 mutations, totaling five unrelated probands (PMID:22325361). A subsequent whole-genome sequencing analysis uncovered a homozygous deep intronic splice variant, c.903+343G>A, in another CSNB pedigree, reinforcing the variant spectrum (PMID:32881472).

Segregation analyses across four families demonstrated co-segregation of GPR179 variants with disease in at least six affected relatives (PMID:22325361; PMID:32881472). All variants—missense, frameshift, and deep intronic—segregated in an autosomal recessive manner with no unaffected carriers exhibiting clinical signs.

Functional assays localized human GPR179 protein to the dendritic tips of ON-bipolar cells and demonstrated that pathogenic missense mutations, including p.His603Tyr, severely reduce cell-surface expression. Splice site and deep intronic variants were shown by minigene and patient-derived cDNA experiments to cause aberrant exonization and premature truncation, which could be rescued by antisense oligonucleotides (PMID:24222301; PMID:32881472).

No conflicting evidence has emerged disputing the role of GPR179 in CSNB; all studies consistently report loss-of-function and concordant electrophysiological phenotypes. Although additional animal models may further elucidate the receptor’s molecular partners, current data sufficiently define the pathogenic mechanism.

Integrated Interpretation

GPR179 is definitively associated with autosomal recessive complete CSNB. Strong genetic evidence (six unrelated probands, segregation in four families, diverse variant classes) and moderate functional evidence (cell localization, splicing rescue) support a loss-of-function mechanism. Testing for both coding and deep intronic GPR179 variants is recommended in diagnostic panels for CSNB.

Key take-home: Biallelic GPR179 mutations cause complete congenital stationary night blindness via haploinsufficiency and aberrant splicing, warranting inclusion in comprehensive genetic testing for CSNB.

References

• American Journal of Human Genetics • 2012 • Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness. PMID:22325361
• Investigative Ophthalmology & Visual Science • 2020 • Phenotype Driven Analysis of Whole Genome Sequencing Identifies Deep Intronic Variants that Cause Retinal Dystrophies by Aberrant Exonization. PMID:32881472
• Investigative Ophthalmology & Visual Science • 2013 • Further insights into GPR179: expression, localization, and associated pathogenic mechanisms leading to complete congenital stationary night blindness. PMID:24222301

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