X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers

X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan

Expression of the CaMKIIβ throughout the brain by AAV-PHP.eB.

Volume-rendered and single-plane images of the brain expressing H2B-mCherry under hSyn1 promoter by the AAV (mCherry, green) counterstained with RD2 (red). A volume-rendered image is shown in the center. Single-plane and magnified images are shown for cerebral cortex, thalamus, hippocampus, midbrain, cerebellum, striatum, and olfactory bulb. Scale bar in the center image, 3 mm; other scale bars, 100 μm. AAV, adeno-associated virus; CaMKIIβ, calmodulin-dependent protein kinase IIβ; hSyn1, human synapsin-1. (TIFF)</p

Robust sleep induction by CaMKIIβ T287D mutant.

(A) Expression levels of endogenous CaMKIIβ and AAV-mediated transduced CaMKIIβ in the brain. Camk2bFLAG/FLAG represents homo knock-in mice in which the FLAG tag was inserted into the endogenous Camk2b locus. PBS: PBS-administrated mice. Immunoblotting against FLAG-tagged protein indicates that AAV-mediated expression of CaMKIIβ is lower than the expression level of endogenous CaMKIIβ. (B) Calculated transduction efficiency plotted against sleep duration. Transduction efficiency is an estimation of the number of AAV vector genomes present per cell in a mouse brain. After the SSS measurements, we purified the AAV vector genomes from the mice brains and then quantified them with a WPRE-specific primer set and normalized to mouse genomes. (C) Sleep transition profiles of mice expressing CaMKIIβ T287-related mutants shown in Fig 1F. The shaded areas represent SEM. (D) Sleep parameters during light or dark period of mice expressing CaMKIIβ T287-related mutants shown in Fig 1F. Multiple comparison tests were performed between all individual groups in each phase. (E, F) Sleep/wake parameters of mice expressing S114-related CaMKIIβ mutants (C) and S109-related CaMKIIβ mutants (D), averaged over 6 days. The shaded areas represent SEM. Multiple comparison tests were performed between all individual groups and resulted in no significant differences. The underlying numerical data can be found in S1 Data, and uncropped or raw image files for S3A Fig are provided in S2 and S3 Data files. Error bars: SEM, *p p p (PDF)</p

Time-of-day analyses for sleep parameters of mice with perturbed CaMKII activity.

(A) Sleep transition profiles of mice expressing the CaMKIIβ del mutant under hSyn1 promoter shown in Fig 2B and 2C. The shaded areas represent SEM. (B) Sleep parameters of mice expressing the CaMKIIβ del mutants shown in Fig 2B and 2C during light or dark period. Multiple comparison tests were performed between all individual groups in each phase. (C) Sleep transition profiles of mice expressing AIP2 or RARA mutant under hSyn1 promoter shown in Fig 2E and 2F. The shaded areas represent SEM. PBS: PBS-injected mice (n = 6). (D) Sleep parameters of mice expressing AIP2 or RARA mutant shown in Fig 2E and 2F during light or dark period. Multiple comparison tests were performed between all individual groups in each phase. The underlying data can be found in S1 Data. Error bars: SEM, *p p p hSyn1, human synapsin-1; (PDF)</p