Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Guanine nucleotide-binding protein subunit beta-3 (GNB3) has been implicated in a unique form of autosomal-recessive congenital stationary night blindness (congenital stationary night blindness) characterised by non-progressive rod photoreceptor and ON bipolar pathway dysfunction. Whole-exome sequencing in a multiplex pedigree and a sporadic CSNB case identified biallelic GNB3 variants, establishing a novel genetic cause of CSNB (PMID:27063057).
Autosomal-recessive inheritance is supported by compound heterozygosity for c.170_172del (p.Lys57del) and c.1017G>A (p.Trp339Ter) in two affected siblings and a homozygous c.1017G>A (p.Trp339Ter) in their maternal aunt, plus an unrelated individual homozygous for c.200C>T (p.Ser67Phe) (PMID:27063057). Segregation of the variants with disease in three relatives confirms co-segregation and pathogenicity.
The variant spectrum includes small in-frame deletions and nonsense and missense mutations: c.170_172del (p.Lys57del), c.1017G>A (p.Trp339Ter), and c.200C>T (p.Ser67Phe). No recurrent or founder alleles beyond the studied families have been reported to date.
Clinically, affected individuals present with lifelong nyctalopia, nystagmus, reduced visual acuity, and high myopia (HP:0000662, HP:0000639, HP:0007663, HP:0011003). Electroretinography demonstrates selective rod dysfunction with variable ON bipolar involvement, distinguishing this form from classic Riggs or Schubert-Bornschein CSNB.
Functional data reveal that GNB3 encodes the Gβ₃ subunit of heterotrimeric G proteins essential for ON bipolar and cone transducin signaling. Mouse models and in vitro studies demonstrate that loss of Gβ₃ disrupts rod and bipolar cell responses, mirroring the human ERG phenotype (PMID:27063057). This mechanistic concordance supports a loss-of-function model in CSNB.
Integration of genetic segregation and functional concordance yields a Strong clinical validity for GNB3 in autosomal-recessive CSNB. Additional families and functional rescue studies would further solidify this association. Key take-home: GNB3 should be included in genetic testing panels for CSNB to guide diagnosis and genetic counseling.
Gene–Disease AssociationStrong4 affected individuals in two families, co-segregation in three relatives, concordant ERG and rod/ON bipolar dysfunction Genetic EvidenceModerateBiallelic GNB3 variants in four probands (compound heterozygous and homozygous), segregation across three relatives in one pedigree Functional EvidenceModerateIn vivo and in vitro models showing loss of Gβ₃ disrupts rod phototransduction and ON bipolar signaling consistent with CSNB |