Night Blindness, Congenital Stationary, Autosomal Dominant 3

A number sign (#) is used with this entry because of evidence that autosomal dominant congenital stationary night blindness-3 (CSNBAD3) is caused by heterozygous mutation in the GNAT1 gene (139330) on chromosome 3p21.

An autosomal recessive form of CSNB (CSNB1G; 616389) is also caused by mutation in the GNAT1 gene.

For a general phenotypic description and discussion of genetic heterogeneity of congenital stationary night blindness, see CSNB1A (310500).

Clinical Features

Dryja et al. (1996) summarized early reports of the most famous family with dominantly inherited night blindness, that descended for some 11 generations from Jean Nougaret (1637-1719), a butcher from Provence who settled in Vendemian, a small village near Montpellier in the south of France. Florent Cunier, the Belgian ophthalmologist who founded Annales d'oculistique, heard of the family, examined some affected members, and stimulated M. Chauvet, a local antiquarian, to assemble the family genealogy. It was Chauvet who showed that Nougaret was the common ancestor of all persons in the district with night blindness. His genealogy listed 629 persons of whom 86 were night blind. Cunier (1838) published the findings. Nettleship (1907) followed up on the family. (An interesting biography of Nettleship was published in JAMA (Anonymous, 1970)). By that time, 135 night-blind persons were known. Vision was unimpaired in daylight, the fundi were normal, and general health was excellent. The excess of normal over affected observed in this family among offspring of affected persons may be a matter of incomplete penetrance or incomplete recording of mild cases--a view subscribed to by the geneticist William Bateson who discussed the paper. Attempts at further follow-up by Dejean and Gassenc (1949) indicated that the village inhabited by Nougaret's descendants was no longer an isolate. Dryja et al. (1996) noted that patients with the Nougaret type of night blindness have no rod a-wave, suggesting a defect inherent in the rod photoreceptors themselves.

Szabo et al. (2007) reported a 3-generation Danish family in which 9 members exhibited typical symptoms of congenital stationary night blindness, with nonprogressive night blindness from early infancy. Four patients who underwent detailed clinical investigation had normal visual acuity and color vision, no constriction of visual fields, and unremarkable fundus examination. Dark adaptometry confirmed complete night blindness in 3 of the patients, whereas the youngest patient exhibited a Riggs-type electroretinographic (ERG) pattern that suggested a presynaptic defect in rod phototransduction. Reexamination of 2 of the 4 patients 20 years later, at the ages of 51 and 57 years, confirmed the nonprogressive nature of the condition. Another family member had constricted visual fields, peripheral hyperpigmentation of the retina, and an extinguished ERG, which are typical symptoms of a degenerative retinopathy such as retinitis pigmentosa (RP; see 268000).

Mapping

In 16 members of a 3-generation Danish family segregating autosomal dominant CSNB, Szabo et al. (2007) performed microsatellite mapping of 3 known CSNBAD loci. Two-point linkage analysis yielded negative scores at 2 of the loci; however, D3S1289, located close to the GNAT1 gene, gave positive lod scores of 1.81 (theta = 0).

Molecular Genetics

Dryja et al. (1996) reported that affected descendants of Jean Nougaret with congenital night blindness carry a missense mutation in the gene encoding the alpha subunit of rod transducin (GNAT1), the G protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade. They analyzed 2 affected sibs for 11 genes in the phototransduction cascade and in both they detected an abnormality in exon 2 of the alpha subunit of rod transducin by SSCP analysis. Sequencing revealed a point mutation in codon 38 (139330.0001) resulting in a G38D amino acid change. No other changes in the coding region or flanking intron sequences were found by SSCP. Dryja et al. (1996) reported that subsequent analysis of 27 relatives revealed that the mutation was present only in affected family members. Dryja et al. (1996) noted that gly38 is a highly conserved residue among heteromeric G proteins including p21(RAS) (see 190020).

In a 3-generation Danish family with autosomal dominant CSNB mapping to chromosome 3p, Szabo et al. (2007) identified a heterozygous missense mutation in the GNAT1 gene (Q200E; 139330.0002), which segregated with the disease and was not found in 104 control alleles. One affected family member who exhibited typical symptoms of RP was heterozygous for the mutation; his daughter, who inherited the mutation, had typical signs of CSNB but no symptoms of RP at age 57 years. Szabo et al. (2007) concluded that the simultaneous occurrence of CSNB and RP in the father was coincidental.