Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

Abstract

X-linked retinitis pigmentosa (XLRP) is the least common genetic type of retinitis pigmentosa; however, it has extremely devastating consequences to patients' activities of daily living. RPGR and RP2 genes expressed in the photoreceptor sensory cilia are predominantly implicated in XLRP; however, the interpretation of genetic mutations and their correlation with clinical phenotypes remain unknown, and the role of these genes in photoreceptor cilia function is not completely elucidated. Therefore, we evaluated structural characteristics in five female obligate carriers of XLRP by using state-of-the-art non-invasive imaging methods, including adaptive optics (AO) scanning laser ophthalmoscopy (SLO). In all five carriers examined, qualitative and quantitative analyses by AO SLO imaging revealed a mosaic pattern of cone disruption, even in the absence of visual symptoms, normal visual acuity and normal macular thickness, on optical coherence tomography and mildly subnormal full-field cone electroretinographic findings. As the technique is sensitive to the level of a single cone, the ability to visualize the cone cells in vivo should be especially useful in other retinal diseases. In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival. European Journal of Human Genetics (2013Genetics ( ) 21, 1240Genetics ( -1248 doi:10.1038/ejhg.2013; published online 27 February 2013Keywords: X-linked retinitis pigmentosa carrier; photoreceptor layer; adaptive optics scanning laser ophthalmoscopy INTRODUCTIONIdentification of X-linked retinitis pigmentosa (XLRP) carriers is challenging and has serious implications for genetic counseling. Female XLRP carriers usually have normal, or close to normal, visual acuity, but often show some degree of fundus changes, including sectorial or peripheral pigmentary deposits and a tapetal-like reflex (TLR), 1 as well as abnormal fundus. Many previous studies have detailed the prevalence of abnormal fundus photography, 1,2 vitreous fluorophotometry, 3 infrared (IR) reflectance images, 1,2 electroretinographic (ERG), 4,5 psychophysical 6 and flicker-fusion 7 findings in such carriers. More recently, several studies have investigated XLRP carriers with advanced devices, including FAF, 8 multifocal ERG 9 and OCT 10,11 to reveal clinical phenotypes of XLRP. Most XLRP carriers can be identified on the basis of fundus findings and ERG changes; however, 10-30% of carriers show no abnormal ERG or fundus finding. 1,4,5,9 Although XLRP is the least common genetic type of RP, accounting for 6-17% of familial retinitis pigmentosa cases, it is extremely devastating. 1,12,13 In the first or second decade of life, affected individuals experience a decrease in peripheral and night vision, and the disease often leads to partial or complete blindness in the fourth or fifth decade of life. 14 In contrast to the severe retinal degeneration in affected men, female carriers of t...

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

“…; Zheng et al. ; Pyo Park et al ). Precision medicine requires highly accurate phenotype–genotype correlations that could be enhanced with new imaging and DNA sequencing modalities.…”

Cone Photoreceptor Abnormalities Correlate With Vision Loss in a Case of Acute Posterior Multifocal Placoid Pigment Epitheliopathy

“…8-10,14 Presumably none of the cones in either the hyperreflective lesions or the dark areas were detected. Unfortunately, neither manual nor automatic calculation methods for cone density have been developed for our second prototype of AO-SLO.…”

“…As the normal appearance of cone cells external to the dark lesions, these lesions may not alter overall visual acuity, which is a function of the entire retina. 14 Also, the dark lesions were too small to be detected by microperimetry. Nonetheless, the decreased autofluorescence on FAF images likely represented a mild reduction in sensitivity attributable to RPE dysfunction.…”

Rapid resolution of retinoschisis with acetazolamide

“…In our previous studies, AOSLO provided rare insight into the cellular organization of retinas in patients with chloroquine retinopathy, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), enhanced S-cone syndrome, and X-linked retinitis pigmentosa (XLRP) [18–21]. Using AOSLO, Duncan et al reported increased cone spacing and abnormal packing in the macula of XLRS patients [22].…”