Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families.
ABSTRACT To characterize the molecular defects in two x-linked retinitis pigmentosa (RP) families. We hypothesized that different RPGR mutations result in distinct RP phenotypes.
Observational case series.
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.
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.
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.
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ABSTRACT: To describe the genotype-phenotype correlation and serial observations in a five-generation Czech family with X-linked retinitis pigmentosa (XLRP) associated with severe visual impairment in women.Molecular vision 01/2014; 20:1307-17. · 2.25 Impact Factor
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ABSTRACT: Hereditary cone disorders (CDs) are characterized by defects of the cone photoreceptors or retinal pigment epithelium underlying the macula, and include achromatopsia (ACHM), cone dystrophy (COD), cone-rod dystrophy (CRD), color vision impairment, Stargardt disease (STGD) and other maculopathies. Forty-two genes have been implicated in non-syndromic inherited CDs. Mutations in the 5 genes implicated in ACHM explain ∼93% of the cases. On the contrary, only 21% of CRDs (17 genes) and 25% of CODs (8 genes) have been elucidated. The fact that the large majority of COD and CRD-associated genes are yet to be discovered hints towards the existence of unknown cone-specific or cone-sensitive processes. The ACHM-associated genes encode proteins that fulfill crucial roles in the cone phototransduction cascade, which is the most frequently compromised (10 genes) process in CDs. Another 7 CD-associated proteins are required for transport processes towards or through the connecting cilium. The remaining CD-associated proteins are involved in cell membrane morphogenesis and maintenance, synaptic transduction, and the retinoid cycle. Further novel genes are likely to be identified in the near future by combining large-scale DNA sequencing and transcriptomics technologies. For 31 of 42 CD-associated genes, mammalian models are available, 14 of which have successfully been used for gene augmentation studies. However, gene augmentation for CDs should ideally be developed in large mammalian models with cone-rich areas, which are currently available for only 11 CD genes. Future research will aim to elucidate the remaining causative genes, identify the molecular mechanisms of CD, and develop novel therapies aimed at preventing vision loss in individuals with CD in the future.Progress in Retinal and Eye Research 05/2014; · 9.90 Impact Factor
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ABSTRACT: Purpose. To provide the first detailed clinical description in patients with retinitis pigmentosa (RP) caused by recessive mutations in IMPG2. Methods. This international collaborative study includes 18 RP patients with inherited retinal disease caused by mutations in IMPG2. All patients were clinically (re-)examined, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, perimetry, electroretinography (ERG), optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, fundus photography, and color vision tests. The main outcome measures included mean age at onset, initial symptom, best-corrected visual acuity, fundus appearance, perimetry results, ERG responses, OCT images, FAF imaging, color vision test reports and DNA sequence variants. Results. The mean age at onset was 11 years (range: 4-23 years). Initial symptoms included night blindness in 61% of patients, a decreased visual acuity in 33% and visual field loss in 6%. Fundus abnormalities were typical of RP: optic disc pallor, attenuated vessels, bone spicules and generalized atrophy of the retina and choriocapillaris. Additionally, we observed macular abnormalities in all patients ranging from mild pigment alterations to profound macular chorioretinal atrophy. A bull's eye maculopathy was observed in seven patients, and macular chorioretinal atrophy in seven patients. Conclusions. Severe mutations in IMPG2 cause RP that generally initiates in the first two decades of life. IMPG2-associated RP is frequently accompanied by macular involvement, ranging from mild pigment alterations to profound macular chorioretinal atrophy. The accompanied decrease in central vision adds to the prominent tunnel vision and results in severe visual impairment in patients with IMPG2-associated RP.Investigative ophthalmology & visual science. 05/2014;