Abstract
Purpose
To report phenotypic progression for a novel mutation in the RPGRgene causing X-linked retinitis pigmentosa (RP), and describe the phenotype in affected males and females
Methods
Bidirectional fluorescent sequencing analysis was used to screen for mutations in RPGR. Five affected males and eight affected females from two English families underwent refraction, ETDRS visual acuity, OCT imaging, and Goldmann visual field testing.
Results
DNA analysis identified a novel c.350G>A sequence change in exon 5 of RPGR. The change segregated with disease in both families. For affected males there was a significant correlation between age and visual acuity (r=−0.91, P=0.034), and a non-significant correlation between age and visual field area (r=−0.56, P=0.4). For affected females, there was a significant correlation between age and visual acuity (r=−0.8, P=0.018), and between age and visual field area (r=−0.94, P=0.005). All affected females were highly myopic. No correlation between retinal thickness, and either age or sex was noted.
Conclusion
This novel mutation in RPGRcauses X-Linked RP with complete penetrance in males and females. Affected females are highly myopic but retain better visual function than affected males. The phenotypic data can be used to provide a mutation-specific visual prognosis, and may also help recognition of the genotype.
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Introduction
X-Linked retinitis pigmentosa (RP) is the least common, but most severe form of RP. In this study, we report phenotypic progression for a novel mutation in exon 5 of RPGR, which causes X-linked RP with complete penetrance, and describe the phenotypic progression in affected males and females.
Methods
Molecular genetic analysis was performed on two English families with a clinical diagnosis of X-linked dominant RP at the National Genetic Reference Laboratory in Manchester, UK (Figure 1). To report the natural history of the phenotype, affected males and females underwent refraction, ETDRS visual acuity, OCT imaging, and Goldmann visual field testing. Data is presented for the right eye unless the right eye had significant co-pathology. Multivariate analysis of covariance was used to test the association of age and sex for each phenotypic variable.
Results
Bidirectional fluorescent sequencing analysis identified the novel sequence change c.350G>A (p.Gly117Glu) at position 117 in exon 5 of RPGR.1 The change segregated with disease in both families, being present in eight affected cases and absent in three unaffected relatives. This glycine residue is conserved across a number of species, and in silico functional analysis suggests that substitution of glycine at residue 117 to glutamic acid is predicted to have a negative effect on the RPGR protein.
Age at examination ranged from 15 to 58 years in the five affected males and 15 to 67 years in the eight affected females (Table 1).
Affected males had refraction from +0.25 D to −10.00 D, ETDRS visual acuity from 75 to 0 letters, foveal thickness from 117 to 224 μm, and V4e Goldmann field area from 11747 mm2 to 0 mm2. There was a significant correlation between age and visual acuity (r=−0.91, P=0.034), and a non-significant correlation between age and visual field area (r=−0.56, P=0.4) (Figure 2).
Affected females had refraction from −7.00 D to −20.00 D, ETDRS visual acuity from 75 to 55 letters, foveal thickness from 144 to 212 μm, and V4e Goldmann field area from 15778 mm2 to 5072 mm2 There was a significant correlation between age and visual acuity (r=−0.8, P=0.018), and between age and visual field area (r=−0.94, P=0.005).
A non-significant trend was observed for affected females to have better visual acuity and field, but to be more myopic than affected males. No association with age or sex was observed for foveal thickness.
Discussion
RPGR mutations are estimated to cause 15–20% of all cases of RP, more than any other single RP locus.2 Traditionally, most RPGR mutations would be considered to be recessive with clinically normal female carriers or heterozygotes. However, some X-linked mutations have a dominant effect with an abnormal phenotype in heterozygous females. For RPGR, this high penetrance in males and females cannot be accounted for by skewed inactivation of the X-chromosome, and seems to be most common with truncating mutations, particularly in exon ORF15.3, 4 In this study, we have shown that X-linked dominant RP can also be the result of a missense mutation in exon 5 of RPGR.
Heterozygous females in X-linked RP families may have no symptoms, but almost 50% may have either a tapetal reflex in the macula or peripheral pigmentary change.2 However, as with other X-linked diseases, some females have symptoms and signs of RP, and are better regarded as being affected, as opposed to being carriers.5 In these two families, complete penetrance was seen in both males and females. Expressivity in heterozygous females was severe, but with later onset loss of acuity and visual field than affected hemizygous males. Although visual acuity remained relatively good into the seventh decade, visual field showed a progressive deterioration with age. The most striking phenotypic feature in affected females was high myopia, with mean refractive error being −14.38 D in females and −4.56 D in males. This feature was noted before either symptoms or signs of retinal degeneration, and may be the earliest and most reliable guide to the affected female status in X-linked dominant RP, its presence implying a mutation in the RPGR gene.2, 3 Heterozygous females had bone spiculation in the mid-peripheral retina. No tapetal reflex was seen and the macula was grossly normal.
Earlier reports have suggested that RP secondary to ORF15 mutations may have a more severe phenotype than RP secondary to mutations elsewhere in the RPGR gene.6, 7 In this study, there was a trend for both visual acuity and visual field to deteriorate with age in both males and females. Despite the small number of subjects, the association was often statistically significant. Limited longitudinal acuity and field data for individuals was in keeping with the pooled trends. This age-related progression must be noted when any comparison is made between the phenotype caused by different mutations. Although other series have suggested that modifier genes may influence the phenotype of RPGR mutations, the strong correlation of acuity and field with age would suggest that genetic and environmental factors have little effect on these parameters in this series, supporting the notion that RP due to mutations in RPGR is a monogenic disorder.8
References
Shu X, Black GC, Rice JM, Hart-Holden N, Jones A, O’Grady A et al. RPGR mutation analysis and disease: an update. Hum Mutat 2007; 28 4: 322–328.
Pelletier V, Jambou M, Delphin N, Zinovieva E, Stum M, Gigarel N et al. Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling. Hum Mutat 2007; 28 1: 81–91.
Rozet JM, Perrault I, Gigarel N, Souied E, Ghazi I, Gerber S et al. Dominant X linked retinitis pigmentosa is frequently accounted for by truncating mutations in exon ORF15 of the RPGR gene. J Med Genet 2002; 39 4: 284–285.
Hong DH, Pawlyk BS, Adamian M, Li T . Dominant, gain-of-function mutant produced by truncation of RPGR. Invest Ophthalmol Vis Sci 2004; 45 1: 36–41.
Dobyns WB . The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked. Acta Paediatr Suppl 2006; 95 451: 11–15.
Sharon D, Bruns G, McGee T, Sandberg M, Berson E, Dryja T . X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest Ophthalmol Vis Sci 2000; 41 9: 2712–2721.
Andréasson S, Breuer D, Eksandh L, Ponjavic V, Frennesson C, Hiriyanna S et al. Clinical studies of X-linked retinitis pigmentosa in three Swedish families with newly identified mutations in the RP2 and RPGR-ORF15 genes. Ophthalmic Genet 2003; 24 4: 215–223.
Walia S, Fishman GA, Swaroop A, Branham KE, Lindeman M, Othman M et al. Discordant phenotypes in fraternal twins having an identical mutation in exon ORF15 of the RPGR gene. Arch Ophthalmol 2008; 126 3: 379–384.
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Al-Maskari, A., O'grady, A., Pal, B. et al. Phenotypic progression in X-linked retinitis pigmentosa secondary to a novel mutation in the RPGR gene. Eye 23, 519–521 (2009). https://doi.org/10.1038/eye.2008.427
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DOI: https://doi.org/10.1038/eye.2008.427
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