Retinal degeneration in mice expressing the constitutively active G90D rhodopsin mutant.

Rhodopsin is the G protein-coupled receptor in rod photoreceptor cells that initiates vision upon photon capture. The light receptor is normally locked in an inactive state in the dark by the covalently bound inverse agonist 11-cis retinal. Mutations can render the receptor active even in the absence of light. This constitutive activity can desensitize rod photoreceptor cells and lead to night blindness. A G90D mutation in rhodopsin causes the receptor to be constitutively active and leads to congenital stationary night blindness, which is generally thought to be devoid of retinal degeneration. The constitutively active species responsible for the night blindness phenotype is unclear. Moreover, the classification as a stationary disease devoid of retinal degeneration is also misleading. A transgenic mouse model for congenital stationary night blindness that expresses the G90D rhodopsin mutant was examined to better understand the origin of constitutive activity and the potential for retinal degeneration. Heterozygous mice for the G90D mutation did not exhibit retinal degeneration whereas homozygous mice exhibited progressive retinal degeneration. Only a modest reversal of retinal degeneration was observed when transducin signaling was eliminated genetically, indicating that some of the retinal degeneration occurred in a transducin-independent manner. Biochemical studies on purified rhodopsin from mice indicated that multiple species can potentially contribute to the constitutive activity causing night blindness.

An inherited night blindness in Wiltshire sheep.

Twelve cases of adult-onset blindness were identified in a flock of 130 polled Wiltshire sheep in New Zealand over a 3-year period. Affected sheep developed night blindness between 2 and 3 years of age, which progressed to complete blindness by 4 to 5 years of age. Fundic examination findings included progressive tapetal hyperreflectivity and attenuation of retinal blood vessels. Histologically, the retinas had a selective loss of rod photoreceptors with initial preservation of cone photoreceptors. Retinal degeneration was not accompanied by any other ocular or central nervous system abnormalities, and pedigree analysis suggested an inherited basis for the disease. Mating an affected Wiltshire ram to 2 affected Wiltshire ewes resulted in 6 progeny that all developed retinal degeneration by 2 years of age, while mating of the same affected ram to 6 unaffected ewes resulted in 8 unaffected progeny, consistent with autosomal recessive inheritance. Homozygosity mapping of 5 affected Wiltshire sheep and 1 unaffected Wiltshire sheep using an OvineSNP50 Genotyping BeadChip revealed an identical-by-descent region on chromosome 5, but none of the genes within this region were considered plausible candidate genes. Whole-genome sequencing of 2 affected sheep did not reveal any significant mutations in any of the genes associated with retinitis pigmentosa in humans or progressive retinal atrophy in dogs. Inherited progressive retinal degeneration affecting rod photoreceptors has not been previously reported in sheep, but this disease has several similarities to inherited retinal dystrophies in other species.

A New Mouse Model for Complete Congenital Stationary Night Blindness Due to Gpr179 Deficiency.

Mutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a Gpr179 knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of Gpr179 disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. Gpr179 knock-out mice exhibit a so-called no-b-wave (nob) phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of Gpr179, GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies.

Sensing through Non-Sensing Ocular Ion Channels.

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a "sensing" ion channel to "non-sensing," leading to ocular channelopathies like Leber's congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a "non-sensing" channel to "sensing" would be life-changing.

Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.

Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the ß subunit of G protein heterotrimer (Gαßγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.

Long-term follow-up of retinal function and structure in TRPM1-associated complete congenital stationary night blindness.

Purpose: TRPM1-associated congenital stationary night blindness (CSNB) is characterized by nystagmus and high myopia. We assessed retinal function and structure over long-term follow-up up to 10 years in two siblings from a family with the homozygous deletion c.2394delC in exon 18 that we previously identified. In addition, we describe retinal function and structure in two other siblings with the novel homozygous c.1394T>A (p.Met465Lys) missense mutation. Methods: Clinical examination included full-field electroretinography, axial length measurements, and multimodal retinal imaging. Molecular genetic tests included next-generation sequencing and Sanger sequencing. Results: All patients had non-recordable rod responses and electronegative configuration of the rod-cone responses at presentation. There was a median of 26% reduction in the dark- and light-adapted electroretinographic (ERG) amplitudes over 4 years. Myopia progressed rapidly in childhood but showed only a mild progression after the teenage years. Visual acuities were stable over time, and there was no sign of progressive retinal thinning. All patients had axial myopia. A novel homozygous c.1394T>A (p.Met465Lys) missense mutation in TRPM1 was identified in two siblings. Conclusions: Further prospective study in larger samples is needed to establish whether there is progressive retinal degeneration in TRPM1-associated CSNB. The associated myopia was found to be mainly axial, which has not been described previously. The mechanism of myopia development in this condition remains incompletely understood; however, it may be related to altered retinal dopamine signaling and amacrine cell dysfunction.

Early onset flecked retinal dystrophy associated with new compound heterozygous RPE65 variants.

Purpose: To report genetic and clinical features of two unrelated Japanese patients with early onset flecked retinal dystrophy. Methods: Patients underwent comprehensive ophthalmic examinations that included electroretinography (ERG) after 30 min and 24 h of dark adaptation (DA). Disease-causing gene variants were identified with whole exome sequencing (WES), with identified candidates confirmed with direct sequencing. Results: WES identified compound heterozygous RPE65 variants in both patients. Variants in patient 1 included c.1543C>T (p.R515W) and c.683A>C (p.Q228P), while patient 2 exhibited c.1028T>A (p.L343*) and c.683A>C (p.Q228P). Although variants p.R515W and p.L343* have been previously reported as pathogenic, variant p.Q228P was reported as uncertain significance. Each unaffected parent carried the variant heterozygously. Both patients had similar ophthalmic findings, including decreased visual acuity with early onset night blindness, numerous dense white dots/flecks occurring mainly outside the vascular arcades, a diffuse and/or disrupted ellipsoid line as shown with optical coherence tomography, and non-recordable rod and combined responses along with decreased cone responses after 30 min of DA. After 24 h of DA, both patients exhibited marked or partial recovery of the combined responses. Conclusions: The results indicate that the recovery of combined or residual cone responses might be associated with a mild form of RPE65-related early onset flecked retinal dystrophy with new compound heterozygous variants.

Maternal uniparental isodisomy of chromosome 6 unmasks a novel variant in TULP1 in a patient with early onset retinal dystrophy.

Purpose: Inherited retinal dystrophies are a clinically and genetically heterogeneous group of disorders. Molecular diagnosis has proven utility for affected individuals. In this study, we report an individual enrolled in the Australian Inherited Retinal Disease Registry and DNA Bank diagnosed with clinical features overlapping between Leber congenital amaurosis and retinitis pigmentosa. Methods: DNA from the proband was sequenced using a gene panel for inherited retinal disorders, and a single nucleotide polymorphism (SNP) array was conducted to detect the presence of deletions and uniparental disomy. Results: We identified a novel homozygous variant (c.524dupC, p.(Pro176ThrfsTer7)) in TULP1 resulting from maternal uniparental isodisomy of chromosome 6. The patient had clinical features consistent with biallelic pathogenic variants in TULP1, including congenital nystagmus, night blindness, non-recordable electroretinogram, mild myopia, and mild peripheral pigmentary changes in the fundus. Conclusions: This is the first report of uniparental disomy 6 and a homozygous variant in TULP1 associated with a rod-cone dystrophy. Molecular diagnosis of inherited retinal dystrophies is essential to inform the mode of transmission and clinical management, and to identify potential candidates for future gene-specific therapies.

Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation.

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results: Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions: The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations.

Inborn Errors of Metabolism: Refsum Disease.

Patient with Refsum disease present with nyctalopia, and the fundus shows progressive panretinal degeneration. Vision gradually decreases, with progressive peripheral constriction. The pupil usually does not dilate well.

A missense mutation in Grm6 reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function.

GRM6 encodes the metabotropic glutamate receptor 6 (mGluR6) used by retinal depolarizing bipolar cells (DBCs). Mutations in GRM6 lead to DBC dysfunction and underlie the human condition autosomal recessive complete congenital stationary night blindness. Mouse mutants for Grm6 are important models for this condition. Here we report a new Grm6 mutant, identified in an electroretinogram (ERG) screen of mice maintained at The Jackson Laboratory. The Grm6nob8 mouse has a reduced-amplitude b-wave component of the ERG, which reflects light-evoked DBC activity. Sequencing identified a missense mutation that converts a highly conserved methionine within the ligand binding domain to leucine (p.Met66Leu). Consistent with prior studies of Grm6 mutant mice, the laminar size and structure in the Grm6nob8 retina were comparable to control. The Grm6nob8 phenotype is distinguished from other Grm6 mutants that carry a null allele by a reduced but not absent ERG b-wave, decreased but present expression of mGluR6 at DBC dendritic tips, and mislocalization of mGluR6 to DBC somas. Consistent with a reduced but not absent b-wave, there were a subset of retinal ganglion cells whose responses to light onset have times to peak within the range of those in control retinas. These data indicate that the p.Met66Leu mutant mGluR6 is trafficked less than control. However, the mGluR6 that is localized to the DBC dendritic tips is able to initiate DBC signal transduction. The Grm6nob8 mouse extends the Grm6 allelic series and will be useful for elucidating the role of mGluR6 in DBC signal transduction and in human disease.NEW & NOTEWORTHY This article describes a mouse model of the human disease complete congenital stationary night blindness in which the mutation reduces but does not eliminate GRM6 expression and bipolar cell function, a distinct phenotype from that seen in other Grm6 mouse models.

Mosaic synaptopathy and functional defects in Cav1.4 heterozygous mice and human carriers of CSNB2.

Mutations in CACNA1F encoding the α1-subunit of the retinal Cav1.4 L-type calcium channel have been linked to Cav1.4 channelopathies including incomplete congenital stationary night blindness type 2A (CSNB2), Åland Island eye disease (AIED) and cone-rod dystrophy type 3 (CORDX3). Since CACNA1F is located on the X chromosome, Cav1.4 channelopathies are typically affecting male patients via X-chromosomal recessive inheritance. Occasionally, clinical symptoms have been observed in female carriers, too. It is currently unknown how these mutations lead to symptoms in carriers and how the retinal network in these females is affected. To investigate these clinically important issues, we compared retinal phenotypes in Cav1.4-deficient and Cav1.4 heterozygous mice and in human female carrier patients. Heterozygous Cacna1f carrier mice have a retinal mosaic consistent with differential X-chromosomal inactivation, characterized by adjacent vertical columns of affected and non-affected wild-type-like retinal network. Vertical columns in heterozygous mice are well comparable to either the wild-type retinal network of normal mice or to the retina of homozygous mice. Affected retinal columns display pronounced rod and cone photoreceptor synaptopathy and cone degeneration. These changes lead to vastly impaired vision-guided navigation under dark and normal light conditions and reduced retinal electroretinography (ERG) responses in Cacna1f carrier mice. Similar abnormal ERG responses were found in five human CACNA1F carriers, four of which had novel mutations. In conclusion, our data on Cav1.4 deficient mice and human female carriers of mutations in CACNA1F are consistent with a phenotype of mosaic CSNB2.

Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness.

PURPOSE: This study was undertaken to investigate the causal mutations responsible for autosomal recessive congenital stationary night blindness (CSNB) in consanguineous Pakistani families. METHODS: Two consanguineous families with multiple individuals manifesting symptoms of stationary night blindness were recruited. Affected individuals underwent a detailed ophthalmological examination, including fundus examination and electroretinography. Blood samples were collected and genomic DNA was extracted. Exclusion analyses were completed by genotyping closely spaced microsatellite markers, and two-point logarithm of odds (LOD) scores were calculated. All coding exons, along with the exon-intron boundaries of GRM6, were sequenced bidirectionally. RESULTS: According to the medical history available to us, affected individuals in both families had experienced night blindness from the early years of their lives. Fundus photographs of affected individuals in both the families appeared normal, with no signs of attenuated arteries or bone spicule pigmentation. The scotopic electroretinogram (ERG) response were absent in all of the affected individuals, while the photopic measurements show reduced b-waves. During exclusion analyses, both families localized to a region on chromosome 5q that harbors GRM6, a gene previously associated with autosomal recessive CSNB. Bidirectional sequencing of GRM6 identified homozygous single base pair changes, specifically c.1336C>T (p.R446X) and c.2267G>A (p.G756D) in families PKRP170 and PKRP172, respectively. CONCLUSIONS: We identified a novel nonsense and a previously reported missense mutation in GRM6 that were responsible for autosomal recessive CSNB in patients of Pakistani decent.

Ophthalmological phenotype associated with homozygous null mutation in the NEUROD1 gene.

PURPOSE: NEUROD1 is a tissue-specific basic helix loop helix (bHLH) protein involved in the development and maintenance of the endocrine pancreas and neuronal elements. Loss of NEUROD1 causes ataxia, cerebellar hypoplasia, sensorineural deafness, and severe retinal dystrophy in mice. Heterozygous loss-of-function mutations in NEUROD1 have previously been described as a cause of maturity-onset diabetes of the young (MODY) and late-onset diabetes. To date, homozygous loss-of-function NEUROD1 mutations have only been detected in two patients. Both mutations caused permanent neonatal diabetes and severe neurologic defects, including visual impairment. However, a detailed ophthalmological phenotype of this novel syndrome has not yet been reported. Our aim was to characterize the ophthalmological phenotype associated with the previously reported homozygous c.427_428CT mutation in the NEUROD1 gene. METHODS: The female patient was investigated on multiple occasions between 2009 (age 14) and 2014 (age 19), including visual acuity testing, automated perimetry, funduscopy, anterior-segment imaging, optical coherence tomography of the posterior pole, standard full-field electroretinography, and fundus-autofluorescence imaging. RESULTS: The patient had nyctalopia, blurry vision, and visual field constriction from early childhood. Her best corrected visual acuity ranged between 20/25 and 15/25 during the investigation period. Perimetry showed concentric constriction of the visual field, sparing only the central 30 degrees in both eyes. The anterior segment did not show any morphological changes. Optical coherence tomography revealed total absence of the photoreceptor layer of the retina outside the fovea, where a discoid remnant of cone photoreceptors could be detected. Neither setting of the standard full-field electroretinography could detect any electrical response from the retina. Color fundus photos presented peripheral chorioretinal atrophy and central RPE mottling. A hyperreflective parafoveal ring was detected on fundus autofluorescent photos, a characteristic sign of hereditary retinal dystrophies. CONCLUSIONS: To the best of our knowledge, this is the first report on the ophthalmological phenotype associating with a homozygous NEUROD1 null mutation in humans. Our results indicate that the loss of NEUROD1 has similar functional and anatomic consequences in the human retina as those described in mice. The present description can help the diagnosis of future cases and provide clues on the rate of disease progression.

NYX mutations in four families with high myopia with or without CSNB1.

PURPOSE: Mutations in the NYX gene are known to cause complete congenital stationary night blindness (CSNB1), which is always accompanied by high myopia. In this study, we aimed to investigate the association between NYX mutations and high myopia with or without CSNB1. METHODS: Four Chinese families having high myopia with or without CSNB1 and 96 normal controls were recruited. We searched for mutations in the NYX gene using Sanger sequencing. Further analyses of the detected variations in the available family members were performed, and the frequencies of the detected variations in 96 normal controls were determined to verify our deduction. The effect of each variation on the nyctalopin protein was predicted using online tools. RESULTS: Four potential pathogenic variations in the NYX gene were found in four families with high myopia with or without CSNB1. Three of the four variants were novel (c.626G>C; c.121delG; c.335T>C). The previously identified variant, c.529_530delGCinsAT, was found in an isolated highly myopic patient and an affected brother, but the other affected brother did not carry the same variation. Further linkage analyses of this family showed a coinheritance of markers at MYP1. These four mutations were not identified in the 96 normal controls. CONCLUSIONS: Our study expands the mutation spectrum of NYX for cases of high myopia with CSNB1; however, more evidence is needed to elucidate the pathogenic effects of NYX on isolated high myopia.

Presence of the Gpr179(nob5) allele in a C3H-derived transgenic mouse.

PURPOSE: To identify the mutation responsible for an abnormal electroretinogram (ERG) in a transgenic mouse line (tg21) overexpressing erythropoietin (Epo). The tg21 line was generated on a mixed (C3H; C57BL/6) background and lacked the b-wave component of the ERG. This no-b-wave (nob) ERG is seen in other mouse models with depolarizing bipolar cell (DBC) dysfunction and in patients with the complete form of congenital stationary night blindness (cCSNB). We determined the basis for the nob ERG phenotype and screened C3H mice for the mutation to evaluate whether this finding is important for the vision research community. METHODS: ERGs were used to examine retinal function. The retinal structure of the transgenic mice was investigated using histology and immunohistochemistry. Inverse PCR was performed to identify the insertion site of the Epo transgene in the mouse genome. Affected mice were backcrossed to follow the inheritance pattern of the nob ERG phenotype. Quantitative real-time PCR (qRT PCR), Sanger sequencing, and immunohistochemistry were used to identify the mutation causing the defect. Additional C3H sublines were screened for the detected mutation. RESULTS: Retinal histology and blood vessel structure were not disturbed, and no loss of DBCs was observed in the tg21 nob mice. The mutation causing the nob ERG phenotype is inherited independently of the tg21 transgene. The qRT PCR experiments revealed that the nob ERG phenotype reflected a mutation in Gpr179, a gene involved in DBC signal transduction. PCR analysis confirmed the presence of the Gpr179(nob5) insertional mutation in intron 1 of Gpr179. Screening for mutations in other C3H-derived lines revealed that C3H.Pde6b(+) mice carry the Gpr179 (nob5) allele whereas C3H/HeH mice do not. CONCLUSIONS: We identified the presence of the Gpr179(nob5) mutation causing DBC dysfunction in a C3H-derived transgenic mouse line. The nob phenotype is not related to the presence of the transgene. The Gpr179(nob5) allele can be added to the list of background alleles that impact retinal function in commonly used mouse lines. By providing primers to distinguish between Gpr179 mutant and wild-type alleles, this study allows investigators to monitor for the presence of the Gpr179(nob5) mutation in other mouse lines derived from C3H.

Night blindness in Sorsby's fundus dystrophy reversed by vitamin A.

Sorsby's fundus dystrophy (SFD) is an autosomal dominant retinal degeneration caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. Mechanisms of the visual loss in SFD, however, remain unknown. In a SFD family with a novel TIMP3 point mutation, we tested a hypothesis that their night blindness is due to a chronic deprivation of vitamin A at the level of the photoreceptors caused by a thickened membrane barrier between the photoreceptor layer and its blood supply. Vitamin A at 50,000 IU/d was administered orally. Within a week, the night blindness disappeared in patients at early stages of disease. Nutritional night blindness is thus part of the pathophysiology of this genetic disease and vitamin A supplementation can lead to dramatic restoration of photoreceptor function.

Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients.

In this study, we investigated the clinical and genetic characteristics of 19 Korean patients with congenital stationary night blindness (CSNB) at two tertiary hospitals. Clinical evaluations, including fundus photography, spectral-domain optical coherence tomography, and electroretinography, were performed. Genetic analyses were conducted using targeted panel sequencing or whole exome sequencing. The median age was 5 (3-21) years at the initial examination, 2 (1-8) years at symptom onset, and 11 (5-28) years during the final visit. Genetic mutations were identified as CNGB1 and GNAT1 for the Riggs type (n = 2), TRPM1 and NYX for the complete type (n = 3), and CACNA1F (n = 14) for the incomplete type. Ten novel variants were identified, and best-corrected visual acuity (BCVA) and spherical equivalents (SE) were related to each type of CSNB. The Riggs and TRPM1 complete types presented mild myopia and good BCVA without strabismus and nystagmus, whereas the NYX complete and incomplete types showed mixed SE and poor BCVA with strabismus and nystagmus. This is the first case series of Korean patients with CSNB, and further studies with a larger number of subjects should be conducted to correlate the clinical and genetic aspects of CSNB.

Optic Atrophy and Inner Retinal Thinning in CACNA1F-related Congenital Stationary Night Blindness.

Hemizygous pathogenic variants in CACNA1F lead to defective signal transmission from retinal photoreceptors to bipolar cells and cause incomplete congenital stationary night blindness in humans. Although the primary defect is at the terminal end of first-order neurons (photoreceptors), there is limited knowledge of higher-order neuronal changes (inner retinal) in this disorder. This study aimed to investigate inner retinal changes in CACNA1F-retinopathy by analyzing macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness and optic disc pallor in 22 subjects with molecularly confirmed CACNA1F-retinopathy. Detailed ocular phenotypic data including distance and color vision, refraction and electroretinogram (ERG) were collected. Distance vision was universally reduced (mean: 0.42 LogMAR), six had abnormal color vision and myopia was common (n = 15; mean: -6.32 diopters). Mean GCL-IPL thickness was significantly lower in patients (55.00 µm) compared to age-matched controls (n = 87; 84.57 µm; p << 0.001). The GCL-IPL thickness correlated with scotopic standard (p = 0.04) and bright-flash (p = 0.014) ERG b/a ratios and photopic b-wave amplitudes (p = 0.05). Twenty-one patients had some degree of disc pallor (bilateral in 19). Fifteen putative disease-causing, including five novel variants were identified. This study establishes macular inner retinal thinning and optic atrophy as characteristic features of CACNA1F-retinopathy, which are independent of myopia and could impact potential future treatment strategies.

High-resolution photoreceptor imaging analysis of patients with autosomal dominant retinitis pigmentosa (adRP) caused by HK1 mutation.

PURPOSE: The hexokinase 1 (HK1) gene encodes one of the four human hexokinases that play essential roles in glucose metabolism. Recently, several cases of E847K mutation in the HK1 gene were reported to cause inherited retinal dystrophy. The purpose of this study was to identify the phenotypical characteristics of patients with a recurrent E847K mutation in the HK1 gene. METHODS: Three generations of one family with autosomal dominant retinitis pigmentosa were examined. Whole exome sequencing was performed on the DNA. Fundus imaging by an adaptive optics fundus camera was used to obtain high-resolution photoreceptor images. RESULTS: Fundus examination of the proband showed degeneration of the mid-peripheral retina, and SD-OCT images showed an absence of the ellipsoid zone (EZ) and interdigitation zone (IZ) in the parafovea and more peripherally. SD-OCT images of the mother of the proband showed an absence of the EZ and IZ, and fundus autofluorescence images showed hypo-autofluorescence surrounding the macular region. One daughter of the proband had only mild night blindness, however, the density of the cone photoreceptors was reduced in the parafoveal region. Whole exome sequencing identified a heterozygous variant, E847K, in the HK1 gene. This variant was found to co-segregate with the disease in three family members. CONCLUSIONS: Although the systemic phenotypes were found to be associated with the HK1 mutations, only the E847K mutation can cause a non-syndromic photoreceptor degeneration. Our study strengthened the hypothesis that the amino acid E847 might play a critical role in the maintenance of the morphology and function of the photoreceptors.