Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families

doi:10.1016/S0002-9394(03)00331-3

American Journal of Ophthalmology

Volume 136, Issue 4, October 2003, Pages 678-687

https://doi.org/10.1016/S0002-9394(03)00331-3 Get rights and content

Abstract

Purpose

To characterize the molecular defects in two x-linked retinitis pigmentosa (RP) families. We hypothesized that different RPGR mutations result in distinct RP phenotypes.

Design

Observational case series.

Methods

Fifteen members in family I and three members in family II were evaluated. Full ophthalmic evaluations were done. Linkage analyses were performed and likelihood of odds scores (LOD score) were calculated. For mutation analyses, we used dHPLC and automated sequencing.

Results

Two novel RPGR mutations were identified in the two families; a Glu 414 (2-bp del) frameshift mutation in family I and an IVS 2–1 (g to a) splice site mutation in family II. All male family members in family I were severely affected by RP but maintained central visual acuities until their 50s and did not develop a bull’s eye maculopathy. The female phenotype was highly variable. Some of the carriers exhibited a severe phenotype, one female displayed an asymmetric phenotype, and other carriers were asymptomatic. All members with the RPGR frameshift mutation exhibited rod-cone electroretinograms abnormalities, whereas five members had hearing loss. Male members of family II were severely affected, with early visual acuity loss, central scotomas, and bull’s eye maculopathy. The female family members were asymptomatic but displayed cone-rod electroretinograms changes. There was no hearing loss.

Conclusions

Different RPGR mutations lead to distinct RP phenotypes, with a highly variable inter- and intrafamilial phenotypic spectrum of disease that is associated with the type of mutation in RPGR and nonrandom X chromosome inactivation, respectively.

Section snippets

Ophthalmic evaluations

Detailed ocular and visual histories were taken, pedigrees were drawn, and detailed eye examinations were performed on all affected and at-risk patients, including age-appropriate best-corrected visual acuities, cycloplegic refractions, slit-lamp biomicroscopy, and dilated indirect ophthalmoscopy. Color vision was tested by D-15 panel and by Ishihara color plates. Visual fields were measured by Goldmann kinetic perimetry, using the V4e and l4e test lights, moving the target from nonseeing to

Family I genotyping

Fifteen family members (9 male, 6 female participants) were phenotyped (Figure 1). All affected members share a Glu414 (2bp del) (bp 1244 to 1245 ΔGA) frameshift mutation in exon 10 of RPGR. This mutation is predicted to result in a stop codon at position 461, and likely represents a null allele.

Male phenotype (n = 9; see Table 1)

Visual acuities ranged from 20/20 (age 25 years) to light perception (age 75 years) but were still 20/40 in two men in their 50s. There was no bull’s eye maculopathy. Cataracts were found in all men

Discussion

As in previous studies,19, 22, 23, 24 we show in our families thatRPGR mutations cause a severe XRRP phenotype in the boys and men with an average onset at age 12 in family I and age 6 in family II. Visual acuities ranged from 20/20 to light perception in family I (with the frameshift mutation), but several male participants maintained 20/40 acuities in their 50s; we did not find a bull’s eye maculopathy. In family II (with the splice site mutation), however, the male phenotype was distinctly

References (24)

D.K. Breuer et al.
A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa
Am J Hum Genet
(2002)
F.Y. Demirci et al.
X-linked cone-rod dystrophy (locus COD1)identification of mutations in RPGR exon ORF15
Am J Hum Genet
(2002)
R.E. Ayyagari et al.
X-linked recessive macular degeneration from RPGR mutation
Genomics
(2002)
S. Grover et al.
A longitudinal study of visual function in carriers of x-linked recessive retinitis pigmentosa
Ophthalmol
(2000)
G.A. Fishman et al.
X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60
Ophthalmology
(1998)
Daiger S. Retnet, 2003. URL: http://www....
A.C. Bird
X-linked retinitis pigmentosa
Br J Ophthalmol
(1975)
R. Vervoort et al.
Mutations of RPGR in X-linked retinitis pigmentosa (RP3)
Hum Mutat
(2002)
R. Vervoort et al.
Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa
Nat Genet
(2000)
A. Meindl et al.
A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3)
Nat Genet
(1996)

D.H. Hong et al.

Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium

J Biol Chem

(2001)

D.B. van Dorp et al.

A family with RP3 type of X-linked retinitis pigmentosaan association with ciliary abnormalities

Hum Genet

(1992)

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X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity.
Cohort study.
Seventy-seven female carriers with RPGR mutations from 41 pedigrees.
Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters.
Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation.
Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002).
Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.
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The prevalence of RP among male patients 20 or younger is approximately twice that of female patients. This finding could be explained by the occurrence of X-linked RP, which is known for its early onset and rapid progression.26–28 In a pedigree analysis of 365 Korean RP patients, X-linked RP accounted for 8.8%, and their use of medical services in their earlier years may have increased the prevalence and cumulative diagnostic rate of male subjects at a younger age.
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Original articleNovel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families

Abstract

Purpose

Design

Methods

Results

Conclusions

Section snippets

Ophthalmic evaluations

Family I genotyping

Male phenotype (n = 9; see Table 1)

Discussion

Am J Hum Genet

Am J Hum Genet

Genomics

Ophthalmol

Ophthalmology

X-linked retinitis pigmentosa

Br J Ophthalmol

Mutations of RPGR in X-linked retinitis pigmentosa (RP3)

Hum Mutat

Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa

Nat Genet

A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3)

Nat Genet

Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium

J Biol Chem

A family with RP3 type of X-linked retinitis pigmentosaan association with ciliary abnormalities

Hum Genet

Original article
Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families