RP2 Phenotype and Pathogenetic Correlations in X-Linked Retinitis Pigmentosa

Department of Ophthalmologyand Visual Sciences, Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA.
Archives of ophthalmology (Impact Factor: 4.4). 07/2010; 128(7):915-23. DOI: 10.1001/archophthalmol.2010.122
Source: PubMed


To assess the phenotype of patients with X-linked retinitis pigmentosa (XLRP) with RP2 mutations and to correlate the findings with their genotype.
Six hundred eleven patients with RP were screened for RP2 mutations. From this screen, 18 patients with RP2 mutations were evaluated clinically with standardized electroretinography, Goldmann visual fields, and ocular examinations. In addition, 7 well-documented cases from the literature were used to augment genotype-phenotype correlations.
Of 11 boys younger than 12 years, 10 (91%) had macular involvement and 9 (82%) had best-corrected visual acuity worse than 20/50. Two boys from different families (aged 8 and 12 years) displayed a choroideremia-like fundus, and 9 boys (82%) were myopic (mean error, -7.97 diopters [D]). Of 10 patients with electroretinography data, 9 demonstrated severe rod-cone dysfunction. All 3 female carriers had macular atrophy in 1 or both eyes and were myopic (mean, -6.23 D). All 9 nonsense and frameshift and 5 of 7 missense mutations (71%) resulted in severe clinical presentations.
Screening of the RP2 gene should be prioritized in patients younger than 16 years characterized by X-linked inheritance, decreased best-corrected visual acuity (eg, >20/40), high myopia, and early-onset macular atrophy. Patients exhibiting a choroideremia-like fundus without choroideremia gene mutations should also be screened for RP2 mutations.
An identifiable phenotype for RP2-XLRP aids in clinical diagnosis and targeted genetic screening.

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Available from: Mohammad I Othman, Oct 04, 2015
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    • "Interestingly, both the affected males had this polymorphic allele, thus supporting the X-linked inheritance pattern. However, we concluded that, in this family, the clinical presentation of the patients probably overlaps with the phenotype of other X-linked retinopathies [Jayasundera et al., 2010; Lee et al., 2003]; alternatively, the CHM phenotype could be caused by mutation of a new, still unknown X-linked gene. Overall, the detection rate (95%) of our procedure is higher than that of other studies in which the causative mutation was identified in approximately two-thirds of European CHM patients screened for defects in the CHM coding region [van den Hurk et al., 1997]. "
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    ABSTRACT: Choroideremia (CHM), an X-linked degeneration of the retinal pigmented epithelium (RPE), photoreceptors, and choroid, ultimately leads to blindness. It is caused by loss-of-function of the CHM gene product, the Rab escort protein 1 (REP1) that is involved, together with its homologue REP2, in prenylation of Rab GTPases, key regulators of intracellular vesicular traffic. Here, we report the molecular characterization of 20 unrelated Italian families affected by CHM. We identified 19 different mutations, nine of which are new. In most cases, we analyzed the effect of the mutations at the mRNA level. Furthermore, we demonstrated, by in vitro trancription/translation assays, that the mutated mRNAs produced truncated proteins in all cases but one. In fact, we also identified a novel REP1 missense variant (c.1520A>G; p.H507R) associated to CHM. Thus far, only two other CHM-associated missense mutations have been identified, one of which was a splicing alteration. We investigated the impact of the p.H507R amino acid change on REP1 structure and function, thus providing the first experimental demonstration that correlates a missense mutation in CHM with a functional impairment of REP1. Overall, our results indicate that the REP1-Rab geranyl-geranyl transferase interaction and consequently REP1-mediated Rab prenylation is essential for RPE and photoreceptor function.
    Human Mutation 12/2011; 32(12):1460-9. DOI:10.1002/humu.21591 · 5.14 Impact Factor
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    • "We and others have reported the association of wide-spectrum of clinical phenotype in patients with RP2 mutations. These clinical features include severe to late-onset disease, typical RP, as well as macular dystrophy [18], [28], [29]. Disease causing mutations in RP2 are presented in the form of splice site, missense, nonsense and/or frameshift variations in the coding region. "
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    ABSTRACT: Genetic mutations are frequently associated with diverse phenotypic consequences, which limits the interpretation of the consequence of a variation in patients. Mutations in the retinitis pigmentosa 2 (RP2) gene are associated with X-linked RP, which is a phenotypically heterogenic form of retinal degeneration. The purpose of this study was to assess the functional consequence of disease-associated mutations in the RP2 gene using an in vivo assay. Morpholino-mediated depletion of rp2 in zebrafish resulted in perturbations in photoreceptor development and microphthalmia (small eye). Ultrastructural and immunofluorescence analyses revealed defective photoreceptor outer segment development and lack of expression of photoreceptor-specific proteins. The retinopathy phenotype could be rescued by expressing the wild-type human RP2 protein. Notably, the tested RP2 mutants exhibited variable degrees of rescue of rod versus cone photoreceptor development as well as microphthalmia. Our results suggest that RP2 plays a key role in photoreceptor development and maintenance in zebrafish and that the clinical heterogeneity associated with RP2 mutations may, in part, result from its potentially distinct functional relevance in rod versus cone photoreceptors.
    PLoS ONE 06/2011; 6(6):e21379. DOI:10.1371/journal.pone.0021379 · 3.23 Impact Factor
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    ABSTRACT: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders. Diagnosis can be challenging as more than 40 genes are known to cause non-syndromic RP and phenotypic expression can differ significantly resulting in variations in disease severity, age of onset, rate of progression, and clinical findings. We describe the clinical manifestations of RP, the more commonly known causative gene mutations, and the genotypic-phenotypic correlation of RP.
    Current Genomics 06/2011; 12(4):267-75. DOI:10.2174/138920211795860116 · 2.34 Impact Factor
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