There have been intermittent reports of X-linked females expressing features of dominant RP. It is well known that females in families with X-linked recessive RP occasionally express partial, often asymmetric ‘carrier’ phenotypes.15–20
The heterogeneity seen in affected carriers in XLRP has been ascribed to lyonisation, the phenomenon in which female carriers randomly inactivate one of their two X-chromosomes, resulting in mosaicism of cells expressing either the normal or mutated X-chromosome.21,22
Radial fundus autofluorescence patterns and a patchy distribution of rod and cone sensitivities observed in the retinas of heterozygotes have been put forth as evidence of the heterogeneous composition of the retinas of female carriers.23,24
Lyonisation mosaicism could explain the occasional severely affected female in families with X-linked recessive RP, but cannot account for the complete and severe penetrance in females from families with X-linked dominant RP, such as UTAD054.
The disease process affecting females in family UTAD054 is fundamentally different than that observed in ‘carrier’ females from families with X-linked recessive RP, in whom disease phenotypes are (usually) more mild and relatively stationary.20
As one would expect with an X-linked dominant disorder, females in this family experienced delayed onset of deterioration but ultimately manifested the full phenotype as measured by clinical examination and testing of visual fields, dark adaptation thresholds, and ERGs. Our report on family UTAD054 represents the only detailed clinical description of a family with an RPGR
X-linked dominant RP with an extended period of observation (as far as 23 years). The few other reports available in literature contain only brief clinical descriptions and little or no follow-up data, but their presence suggests that family UTAD054 is not alone. Rozet et al12
identified 14 families in which carrier females also had findings consistent with RP, sometimes equally affected as their male counterparts. All 14 families had linkage analysis data supporting localisation to the RP3 region, with 9 of the 14 families (and all five of the families whose female members were affected as equally as males) having mutations identified in exon ORF15 of RPGR
. Banin et al10
reported on one family with a missense mutation in exon 8 of the RPGR
gene in whom carrier females, as well as males, also consistently showed loss of visual acuity, visual field, and decreased ERG ampltudes. In their study on RPGR
gene mutations, Neidhardt et al11
identified three families with affected females and a presumed autosomal dominant pattern that were subsequently found to have mutations in ORF15. Most recently, Al-Maskari et al9
reported on two English families with a missense mutation in exon 5 of the RPGR
gene, in which both females and males showed severe deterioration in visual acuity, visual field, and high myopia with age.
To date, the only similar report of dominant XLRP not involving an RPGR
mutation has come from Pomares et al25
, who characterised a family with an intronic point mutation in RP2
that results in aberrant splicing and a truncated protein. All males had uniformly high aberrant RP2
transcripts and a clear RP phenotype, whereas three of the four carrier females had variably high levels of aberrant transcripts and two of the carrier females had mild-to-moderate progressive deterioration in fundus appearance, visual field, and ERG. Pomares et al
categorised this family as having a ‘semi-dominant’ phenotype and suggested that skewed X-inactivation could be the cause. As this is the first report of such an inheritance pattern associated with RP2
, the hypothesis of skewed X-inactivation needs to be tested in other semi-dominant families with RP2
mutations, as they are discovered. Pelletier et al5
have already studied the X-inactivation pattern in 55 women from 28 RPGR mutation families in which several carrier females complained of severe visual impairment. Of those tested, 54 out of 55 had a random inactivation of the X-chromosome and only one of the 55 had skewed X-inactivation. Furthermore, when the other four carriers in her family were tested, they were found to have random patterns of X-inactivation. Thus, skewed inactivation may represent a rare event in these families and is not likely to represent the primary reason behind severe phenotypes in females with RPGR
The fact that nearly all reports of a dominant pattern of inheritance have been associated with mutations in the RPGR
gene argues that some specific aspect of RPGR
mutations may lead to higher penetrance in females. In general, such a phenotypic difference can be attributed to at least two causes. First, the penetrance and expressivity of the phenotype may be modified by the presence of a modifier allele in a completely different gene that is inherited. Interactions between the mutation in RPGR
and additional modifiers are likely to be important determinants of the phenotype. We have earlier shown that RPGR exists in multiprotein complexes in photoreceptors26
and hypothesise that a partial loss of function mutation in the protein partners can affect the penetrance and expressivity of the disease.27
Recently, we identified a hypomorphic mutation in the ciliary protein RPGR-interacting protein 1-like (RPGRIP1 L/NPHP8), which significantly affects its interaction with RPGR and is associated with the penetrance of the retinal degeneration phenotype in patients with syndromic ciliopathies.28
We hypothesise that single allelic mutations may affect this mechanism and could occur on a dominant basis in females. Second, the effect of the specific RPGR–ORF15
mutation per se
is such that the mutant protein behaves in a dominant gain-of-function manner and results in a more severe phenotype in both males and females. Support for this hypothesis comes from an earlier demonstration by Hong et al29
that a naturally occurring RPGR variant with an in-frame deletion in exon ORF15 in transgenic mice is associated with more severe progression of the disease in the RPGR
knockout as well as wild-type background. Moreover, two canine models of XLRP carrying mutations in RPGR–ORF15
have also been reported to show discordant phenotypes, with one being more severely affected than the other.30
With a predicted dominant, gain-of-function mutation, the random inactivation of some abnormal X-chromosomes in carrier females may provide some initial protection compared with males who possess only the mutant version. However, this may not be sufficient to ameliorate the disease phenotype over time. An additional analysis of animal models will be required to completely understand the phenotypic heterogeneity.
The high number of female members of family UTAD054 with severe disease is clearly different than the more sporadic nature of affected carriers with X-linked recessive RP, but how does it compare with other diseases that are classified as being inherited in an X-linked dominant manner? A recent review of X-linked disorders discussed the utility of considering penetrance and severity in the discussion of such diseases.31
Of the 32 X-linked disorders reviewed in that study, there was a bimodal distribution of penetrance in carrier females, with most disorders having either 0–10% or 90–100% penetrance of the mutation. Interestingly, the severity index (which the authors defined as the proportion of all symptomatic individuals with a severe phenotype) was above 70% in only three of these disorders, all of which were classically considered X-linked dominant. Family UTAD054 then resembles other X-linked dominant disorders because there is complete penetrance of a severe RP phenotype in 100% of adult female mutation carriers. There are several reports of XLRP families with mutations in RPGR
in which penetrance is high in heterozygote females, but with a large variance in severity.24,32–35
Part of the difficulty in extrapolating penetrance and severity from other reports in the literature is because of limitations in the number of family members available for examination and subsequent follow-up. The large size of family UTAD054 and the extended period of time in which we could follow its members enabled us to document the progressive nature of their disease, in contrast to the more stable carrier phenotype associated with the X-linked recessive disease. It would be interesting to see how many female heterozygotes in other studies progressed in severity over time as the affected female members of family UTAD054 did.
In summary, we provide a detailed clinical description of a large XLRP family with an RPGR–ORF15 mutation in which both female and male members of this family develop severe forms of the disease that progressively worsened with time. The identification and study of additional families with X-linked dominant inheritance is important for several reasons. Over the long term, clarifying the mechanism(s) that determine penetrance and severity in female members of families with XLRP will allow a better understanding of the pathogenesis of XLRP. Of more immediate concern, families with dominant-acting RPGR
mutations may be mistaken as having an autosomal mode of inheritance resulting in an incorrect prediction of recurrence risk and errors in prognosis. As RPGR
mutations are believed to account for over 70% of families with XLRP, our report is relevant to many patients.3,4,36
A broader recognition that XLRP has both a dominant and recessive inheritance mechanism is not merely a matter of semantics, but has important implications for genetic counselling in such families.
What was known before
- X-linked retinitis pigmentosa has typically been associated with a severe phenotype in males and a variable, often more mild phenotype in females. The wide range of severity among carrier females was felt to be related to random inactivation of the normal X-chromosome.
What this study adds
- Some forms of X-linked retinitis pigmentosa can be associated with a highly penetrant phenotype which can inevitably affect all carrier females in a family. These appear to be associated with mutations particularly in RPGR. Without careful attention, they may be mistaken as autosomal dominant retinitis pigmentosa.