Bessant et al. (1999) identified a large 3-generation British family (RP251) segregating autosomal dominant retinitis pigmentosa and excluded previously identified autosomal dominant loci. Bessant et al. (1999) identified a heterozygous mutation in the NRL gene in affected members ... Bessant et al. (1999) identified a large 3-generation British family (RP251) segregating autosomal dominant retinitis pigmentosa and excluded previously identified autosomal dominant loci. Bessant et al. (1999) identified a heterozygous mutation in the NRL gene in affected members (see MOLECULAR GENETICS). Bessant et al. (2000) identified 3 other British RP families who carried the same mutation and determined that all 4 families were descended from a common founder. In all 4 families the phenotype was fully penetrant and exhibited only limited variability. Early severe loss of rod function with preserved cone function and a very high incidence of macular edema were the characteristic features. To further define the phenotype associated with the NRL S50T mutation (162080.0001), Bessant et al. (2003) performed detailed clinical, electrophysiologic, and psychophysical studies of 25 members of the original family (14 affected members, 7 unaffected, and 4 spouses). They also obtained information from clinical records for 8 individuals from the 3 families identified by Bessant et al. (2000). Bessant et al. (2003) identified 7 characteristic features of the phenotype that in combination would suggest an underlying NRL mutation. The S50T mutation causes a severe progressive retinal dystrophy affecting first the rod and subsequently the cone photoreceptors. While rod function is profoundly impaired in the first 2 decades of life, cone function remains relatively well preserved at this stage. Significant loss of cone function occurs as the disorder progresses, and in older individuals, all components of the electroretinogram are nondetectable. Patients almost invariably develop macular thickening, frequently with a mild reduction in visual acuity, between ages 15 and 30 years. As the disease progresses, a substantial loss of visual acuity is usually observed, typically in association with the development of a bull's-eye pattern of macular atrophy. Peripheral intraretinal pigment formation is sparse, even in the later stages of the disease. Distinctive peripapillary chorioretinal atrophy develops as the dystrophy progresses.
In a 3-generation British family with autosomal dominant retinitis pigmentosa, Bessant et al. (1999) identified a heterozygous missense mutation in the NRL gene (S50T; 162080.0001). Bessant et al. (2000) identified the S50T mutation in 3 additional families and ... In a 3-generation British family with autosomal dominant retinitis pigmentosa, Bessant et al. (1999) identified a heterozygous missense mutation in the NRL gene (S50T; 162080.0001). Bessant et al. (2000) identified the S50T mutation in 3 additional families and showed that all 4 families carrying the mutation were descended from a common founder. Hernan et al. (2012) screened the NRL gene in 50 Spanish autosomal dominant RP probands and identified a heterozygous missense mutation in 1 (M96T; 162080.0004). The proband's mother and a maternal aunt were also heterozygous for the mutation; all 3 developed night blindness in the second or third decade of life, a later onset of disease than previously reported with mutations in the NRL gene. In vitro functional analysis showed that the M96T mutant increased transactivation to a lesser degree than the S50T or P51L (see Martinez-Gimeno et al., 2001) mutant proteins. In addition, the proband's sister and a cousin carried the mutation but remained asymptomatic at ages 37 and 45 years, respectively. Hernan et al. (2012) suggested that the NRL mutation might not be the sole cause of RP in this family; however, analysis of 550 retinal candidate genes by DNA capturing and massive next-generation sequencing did not reveal any other genomic variation that cosegregated with RP in the family.