Photoreceptors rely on microtubule (MT)-based transport within the connecting cilium to maintain cellular homeostasis. Mutations in RP1L1, a retina-specific doublecortin (DC) domain protein, cause inherited retinal disorders including occult macular dystrophy (OMD), yet the underlying mechanisms remain poorly defined. Here, we show that the RP1L1 R45W variant, prevalent in East Asian individuals with OMD, confers a toxic gain-of-function phenotype characterized by abnormally strong MT binding. Live-cell imaging revealed an approximately twofold increase in MT association relative to wild-type RP1L1. Molecular dynamics simulations indicated that R45W stabilizes RP1L1-α-tubulin interactions via cation-π contacts and reduced electrostatic repulsion. Remarkably, low concentrations of glycerol selectively disrupted these aberrant interactions, restoring MT binding to wild-type levels in both cellular and biochemical contexts. Our study elucidates a structural and mechanistic basis for RP1L1 R45W hyper-binding and demonstrates that small-molecule modulation of DC-domain interactions might provide a variant-specific therapeutic strategy for RP1L1-related retinopathies.

Occult macular dystrophy (OMD) is a hereditary macular disease characterized by no visible macular abnormalities. It is an autosomal dominant disease associated with retinitis pigmentosa 1 like 1 (RP1L1) gene mutation. c.133C > T mutation in the RP1L1 gene is the primary cause of severe visual impairment in OMD patients. The induced pluripotent stem cell (iPSC) line was generated using the integration-free Sendai virus method from peripheral blood mononuclear cells (PBMCs) of a vision-impaired patient harboring heterozygous RP1L1 c.133C > T mutation. This cell line may serve as a cellular model for studying the pathogenic mechanisms of OMD caused by RP1L1 mutation.

Head-mounted ("virtual reality") perimeters (HMPs), based on standard consumer electronic hardware, are a cheaper alternative to standard automated perimetry. They have not been validated in patients with inherited retinal disease (IRDs), yet. We evaluated the Iowa-HMP in a first pilot study. It consists of a legacy smartphone, a headset, and freely available, open-source software. We used the 10-2 grid, the ZEST algorithm, and a background of 10 cd/m2 to measure central visual fields in one normal subject, and in patients with occult macular dystrophy (n = 2), Stargardt's disease (n = 3) and retinitis pigmentosa (n = 6). Results were compared with those from an Octopus 900 perimeter. The typical patterns of visual field loss were clearly discernible, but head-mounted perimeters generally have a limited dynamic range. Within the dynamic range of the Iowa-HMP (14 to 30 dB Octopus sensitivity), the Limits of Agreement (Bland-Altman) were ±7.5 dB. The Iowa-HMP had a diagnostic sensitivity of 0.67 for detecting locations with low perimetric sensitivity (<14 dB in the Octopus perimetry) with a diagnostic specificity of 0.95. Although the Iowa-HMP cannot be directly compared to standard perimetry in IRDs, open software greatly facilitates research in this area.

In the past, only Oguchi disease was reported as a hereditary retinal disease from Japan. Dr. Chuuta Oguch was a Professor of Nagoya University in Japan. During the past 40 years, four new clinical entities in hereditary retinal disorders have been detected by the Miyake group from Nagoya, Japan. All disorders show essentially normal fundi, and the diagnosis was made mainly by the analysis of an electroretinogram (ERG). Gene mutations are detected in three of them. Bipolar cell (BP) dysfunction syndrome: Congenital stationary night blindness (CSNB) with negative ERG (a-wave is larger than b-wave) was named as the Schubert-Bornschein type in 1952 and considered to be an independent clinical entity. In 1986, Miyake group classified ninety patients with the Schubert-Bornschein type into two types (complete and incomplete type). The complete type of CSNB (CSNB1) showed no rod function, but the incomplete type CSNB (CSNB2) showed remaining rod function in both subjective dark adaptation and rod ERG. In order to investigate the pathogenesis, these two types of CSNB were analyzed by comparing the monkey ERGs using different glutamate analogs to the retina. The ERG analysis demonstrated that CSNB1 has a complete functional defect in the ON type BP, while CSNB2 has incomplete functional defects in the ON and OFF type BP in both rod and cone visual pathways. Evidence of several different genetic heterogeneities was reported in both diseases, indicating CSNB1 and CSNB2 are independent clinical entities. Another entity, showing total complete defect of both ON and OFF BP, was detected in 1974 and was reported by Miyake group in a brother and younger sister, showing severe photophobia, nystagmus, extremely low visual acuity, and disappearance of color vision (total color blindness). This disorder is a congenital stational condition, and subjective visual functions were severely deteriorated from birth but remained unchanged through life. This disease was termed "Total complete bipolar cell dysfunction syndrome (CSNB3)". The relationship between BP and subjective visual function was unknown. These three kinds of BP diseases can provide information on how BP relates to subjective visual functions. Occult macular dystrophy (OMD): Occult macular dystrophy (OMD) was discovered by Miyake group in 1989. This disease shows an unusual, inherited macular dystrophy characterized by progressive decrease visual acuity due to macular dysfunction, but the fundus and fluorescein angiography are essentially normal. The full-field rod and cone ERG do not show any abnormality, but the focal macular ERG (FERG) or multifocal ERG is abnormal and the only method for diagnosis. Many pedigrees of this disorder suggest autosomal dominant heredity, showing a genetic mutation of RP1L1. This disease was termed "occult macular dystrophy". "Occult" means "hidden from sight". Recently, it has been called "Miyake disease".

To identify patterns of functional defects in perifoveal photoreceptor-directed temporal contrast sensitivities (tCSs) in patients with inherited retinal diseases. We retrospectively studied patients with RP1L1-associated occult macular dystrophy (OMD), Stargardt disease (STGD), and RP. Photoreceptor-directed tCS directed at L-, M-, S-cones and rods at different temporal frequencies were measured using a four-primary LED-stimulator with an annular test field (2° inner diameter and 12° outer diameter). Mean defects (MDs) were calculated by subtracting sensitivities from age-correlated normal values and averaging defects in frequency ranges where single postreceptoral pathways mediate flicker detection. Each patient was characterized by 6 MD values (one value each for S-cones [SMD] rods [RMD]; two values each for L- [LMDlow/high] and M-cones [MMDlow/high], where low refers to 1-6 Hz and high to 8-20 Hz temporal frequency ranges). Groups of similar phenotypes were identified with (supervised) decision trees and (unsupervised) hierarchical classification trees (based on nearest neighbors) and compared with the clinical diagnoses. The pruned decision tree used RMD for separating RP/STGD from normal/OMD, LMDlow for separating OMD from normal, and SMD for discriminating between RP and STGD. The accuracy was 66%. The hierarchical tree (independent of clinical diagnosis) was cut to four clusters, resulting in one cluster containing mainly normal participants, one cluster with severe L- and M-cone defects caused by OMD or STGD, one cluster with severe rod defects (4/5 with RP) and a large cluster with intermediate rod and cone defects that was dominated by RP and STGD patients. LMDlow, SMD, and RMD were the most important parameters. Photoreceptor-directed tCSs allow sophisticated functional phenotyping of inherited retinal diseases and complement other structural and functional parameters for genotype-phenotype correlations.