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Investigative Ophthalmology & Visual... Jun 2022We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.
PURPOSE
We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.
METHODS
AL measurements from IRD natural history study participants were included and compared with reference cohorts (TwinsUK, Raine Study Gen2-20, and published studies). Comparing with the Raine Study cohort, formal odds ratios (ORs) for AL ≥ 26 mm or AL ≤ 22 mm were derived for each IRD (Firth's logistic regression model, adjusted for age and sex).
RESULTS
Measurements were available for 435 patients (median age, 19.5 years). Of 19 diseases, 10 had >10 participants: ABCA4 retinopathy; CNGB3- and CNGA3-associated achromatopsia; RPGR-associated disease; RPE65-associated disease; blue cone monochromacy (BCM); Bornholm eye disease (BED); TYR- and OCA2-associated oculocutaneous albinism; and GPR143-associated ocular albinism. Compared with the TwinsUK cohort (n = 322; median age, 65.1 years) and Raine Study cohort (n = 1335; median age, 19.9 years), AL distributions were wider in the IRD groups. Increased odds for longer ALs were observed for BCM, BED, RPGR, RPE65, OCA2, and TYR; increased odds for short AL were observed for RPE65, TYR, and GPR143. In subanalysis of RPGR-associated disease, longer average ALs occurred in cone-rod dystrophy (n = 5) than rod-cone dystrophy (P = 0.002).
CONCLUSIONS
Several diseases showed increased odds for longer AL (highest OR with BCM); some showed increased odds for shorter AL (highest OR with GPR143). Patients with RPE65- and TYR-associated disease showed increased odds for longer and for shorter eyes. Albinism genes were associated with different effects on AL. These findings add to the phenotype of IRDs and may yield insights into mechanisms of refractive error development.
Topics: ATP-Binding Cassette Transporters; Albinism, Oculocutaneous; Eye Proteins; Genetic Diseases, X-Linked; Humans; Mutation; Myopia; Retina; Retinal Diseases
PubMed: 35704304
DOI: 10.1167/iovs.63.6.15 -
The CRISPR Journal Jun 2022Mutations in the gene cause X-linked ocular albinism type 1 (OA1), a disease that severely impairs vision. We recently generated induced pluripotent stem cells (iPSCs)...
Mutations in the gene cause X-linked ocular albinism type 1 (OA1), a disease that severely impairs vision. We recently generated induced pluripotent stem cells (iPSCs) from skin fibroblasts of an OA1 patient carrying a point mutation in intron 7 of . This mutation activates a new splice site causing the incorporation of a pseudoexon. In this study, we present a high-performance CRISPR-Cas ribonucleoprotein strategy to permanently correct the mutation in these patient-derived iPSCs. Interestingly, the two single-guide RNAs available for SpCas9 did not allow the cleavage of the target region. In contrast, the cleavage achieved with the CRISPR-AsCas12a system promoted homology-directed repair at a high rate. The CRISPR-AsCas12a-mediated correction did not alter iPSC pluripotency or genetic stability, nor did it result in off-target events. Moreover, we highlight that the disruption of the pathological splice site caused by CRISPR-AsCas12a-mediated insertions/deletions also rescued the normal splicing of and its expression level.
Topics: Albinism, Ocular; CRISPR-Cas Systems; Eye Proteins; Gene Editing; Humans; Induced Pluripotent Stem Cells; Membrane Glycoproteins; Mutation
PubMed: 35686978
DOI: 10.1089/crispr.2021.0110 -
Clinical Ophthalmology (Auckland, N.Z.) 2022Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular... (Review)
Review
Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular abnormalities. The main ocular features common to both oculocutaneous albinism (OCA), and ocular albinism (OA) include reduced visual acuity, refractive errors, foveal hypoplasia, congenital nystagmus, iris and fundus hypopigmentation and visual pathway misrouting, but clinical signs vary and there is phenotypic overlap with other pathologies. This study reviews the prevalence, genetics and ocular manifestations of OCA and OA, including abnormal development of the optic chiasm. The role of visual electrophysiology in the detection of chiasmal dysfunction and visual pathway misrouting is emphasized, highlighting how age-associated changes in visual evoked potential (VEP) test results must be considered to enable accurate diagnosis, and illustrated further by the inclusion of novel VEP data in genetically confirmed cases. Differential diagnosis is considered in the context of suspected retinal and other disorders, including rare syndromes that may masquerade as albinism.
PubMed: 35637898
DOI: 10.2147/OPTH.S329282 -
Frontiers in Molecular Biosciences 2022GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G... (Review)
Review
GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G protein-coupled receptors (GPCRs) hold the potential to pave the way for development of new, innovative therapeutic strategies. In this review we will introduce G protein-coupled receptor 143 (GPR143), an enigmatic receptor in terms of classification within the GPCR superfamily and localization. GPR143 has not been assigned to any of the GPCR families due to the lack of common structural motifs. Hence we will describe the most important motifs of classes A and B and compare them to the protein sequence of GPR143. While a precise function for the receptor has yet to be determined, the protein is expressed abundantly in pigment producing cells. Many GPR143 mutations cause X-linked Ocular Albinism Type 1 (OA1, Nettleship-Falls OA), which results in hypopigmentation of the eyes and loss of visual acuity due to disrupted visual system development and function. In pigment cells of the skin, loss of functional GPR143 results in abnormally large melanosomes (organelles in which pigment is produced). Studies have shown that the receptor is localized internally, including at the melanosomal membrane, where it may function to regulate melanosome size and/or facilitate protein trafficking to the melanosome through the endolysosomal system. Numerous additional roles have been proposed for GPR143 in determining cancer predisposition, regulation of blood pressure, development of macular degeneration and signaling in the brain, which we will briefly describe as well as potential ligands that have been identified. Furthermore, GPR143 is a promiscuous receptor that has been shown to interact with multiple other melanosomal proteins and GPCRs, which strongly suggests that this orphan receptor is likely involved in many different physiological actions.
PubMed: 35495622
DOI: 10.3389/fmolb.2022.873777 -
Frontiers in Genetics 2022is a nuclear transcription factor gene that is highly conserved among species. Variants within could result in optic nerve colobomas and kidney hypoplasia. However,...
is a nuclear transcription factor gene that is highly conserved among species. Variants within could result in optic nerve colobomas and kidney hypoplasia. However, little clinical and genetic information is currently available about variants in Chinese children. This study aims to further understand the clinical manifestations and genetic characteristics of variants in Chinese population. In this single-center retrospective study, we analyzed the clinical data of 10 children identified as carriers of variants by gene sequencing. All the variants found in this study were analyzed using prediction and American College of Medical Genetics and Genomics (ACMG) standards and guidelines. The mean age for developing the first symptom in 10 unrelated children was 7.2 years old. Proteinuria and bilateral kidney dysplasia were found in every patient. Two children underwent kidney histological examination; one child showed high-intensity C1q deposition in the kidney, and the other child showed focal segmental glomerular sclerosis (FSGS). Three children had -related ocular abnormalities, including nystagmus, retinal exudation, amblyopia, microphthalmia, microcornea, and total blindness. In addition, one patient had the comorbidity of oculocutaneous albinism (OCA). Eight different variants were found in ten patients, three of which were reported for the first time. We reported some patients with unique manifestations and comorbidities, and we reported three variants that have not been previously identified. The gene is prone to spontaneous variants, and the outcome of patients is unfavorable. Because of the lack of specific therapy, genetic testing should be recommended for individuals with obvious evidence of kidney dysplasia and eye abnormalities, and kidney protective treatment should be initiated early.
PubMed: 35444690
DOI: 10.3389/fgene.2022.799562 -
Ophthalmology Jun 2022To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). (Observational Study)
Observational Study
PURPOSE
To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH).
DESIGN
Multicenter, observational study.
PARTICIPANTS
A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384).
METHODS
Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans.
MAIN OUTCOME MEASURES
Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA).
RESULTS
The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH.
CONCLUSIONS
We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.
Topics: Albinism; Albinism, Ocular; Albinism, Oculocutaneous; Color Vision Defects; Cytoskeletal Proteins; Fovea Centralis; Humans; Membrane Proteins; Vision Disorders
PubMed: 35157951
DOI: 10.1016/j.ophtha.2022.02.010 -
Journal of AAPOS : the Official... Jun 2022Anterior megalophthalmos is a form of anterior segment dysgenesis characterized by megalocornea (>12.5 mm) coupled with an enlarged lens-iris diaphragm and ciliary body...
Anterior megalophthalmos is a form of anterior segment dysgenesis characterized by megalocornea (>12.5 mm) coupled with an enlarged lens-iris diaphragm and ciliary body ring. Importantly, intraocular pressure (IOP) is normal, and in contrast to buphthalmos, the ratio of anterior segment to vitreous cavity measurements is increased. Anterior megalophthalmos may be an isolated ocular finding, or it may be associated with syndromes such as albinism, Down syndrome, Frank-Ter-Haar, Marfan, Neuhauser, mucolipidosis type 2, and osteogenesis imperfecta. We report anterior megalophthalmos in 2 sisters with genetically confirmed (SIN3A, c.1657C>T, p.R553∗) Witteveen-Kolk syndrome (OMIM #613406).
Topics: Eye Abnormalities; Eye Diseases, Hereditary; Female; Genetic Diseases, X-Linked; Humans; Hydrophthalmos; Iris
PubMed: 35144002
DOI: 10.1016/j.jaapos.2022.01.003 -
Frontiers in Pharmacology 2021Hermansky-Pudlak syndrome (HPS), a rare heterogeneous autosomal recessive disorder, is characterized by oculocutaneous albinism (OCA) and a bleeding diathesis due to a...
Hermansky-Pudlak syndrome (HPS), a rare heterogeneous autosomal recessive disorder, is characterized by oculocutaneous albinism (OCA) and a bleeding diathesis due to a defect regarding melanosomes and platelet delta (δ)-granule secretion. Interestingly, patients with HPS type 2 (HPS-2) or HPS type 10 (HPS-10) present additionally with an immunological defect. We investigated three patients (IP1, IP2, and IP3) who suffer from a bleeding diathesis. Platelet aggregometry showed impaired platelet function and flow cytometry revealed a severely reduced platelet CD63 expression hinting to either a defect of platelet delta granule secretion or a decreased number of delta granules in these patients. However, only IP3 presents with an apparent OCA. We performed panel sequencing and identified a homozygous deletion of exon 6 in for IP3 Western analysis confirmed the absence of the encoded protein dysbindin confirming the diagnosis of HPS-7. Interestingly, this patient reported additionally recurrent bacterial infections. Analysis of lymphocyte cytotoxicity showed a slightly reduced NK-degranulation previously documented in a more severe form in patients with HPS-2 or HPS-10. IP1 is carrier of two compound heterozygous variants in the gene (c.65C > G and c.1193G > A). A homozygous variant in (c.760G > T) was identified in IP2. The novel missense variants were classified as VUS (variant of uncertain significance) according to ACMG guidelines. For IP1 with the compound heterozygous variants in a specialized ophthalmological examination showed ocular albinism. and encode subunits of the BLOC-2 complex and patients with HPS-3 or HPS-5 are known to present with variable/mild hypopigmentation.
PubMed: 35126127
DOI: 10.3389/fphar.2021.786937 -
Therapeutic Advances in Ophthalmology 2022Foveal hypoplasia is the absence of a foveal depression and the presence of the ganglion cell layer in the foveola. A spectrum of clinical characteristics, including... (Review)
Review
Foveal hypoplasia is the absence of a foveal depression and the presence of the ganglion cell layer in the foveola. A spectrum of clinical characteristics, including normal or variably decreased visual acuity, has been described in patients with blunted foveal contours. Multiple systemic and ophthalmologic conditions including albinism, aniridia, nanophthalmos, prematurity, and fovea plana have been associated with this anomaly. This article illustrates select clinical conditions characterized by a blunted foveal contour. Given the heterogeneity of findings, a thorough medical history and detailed physical and ocular examinations are usually sufficient for the clinician to make the correct diagnosis.
PubMed: 35083420
DOI: 10.1177/25158414211070864 -
Investigative Ophthalmology & Visual... Jan 2022The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities... (Comparative Study)
Comparative Study
PURPOSE
The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities (FHONDA syndrome), to describe the phenotypic spectrum, and to compare it to albinism.
SUBJECTS AND METHODS
We retrospectively collected molecular, ophthalmic, and electrophysiological data of 28 patients molecularly confirmed with FHONDA from the Netherlands (9), Israel (13), France (2), and the United States of America (4). We compared the data to that of 133 Dutch patients with the 3 most common types of albinism in the Netherlands: oculocutaneous albinism type 1 (49), type 2 (41), and ocular albinism (43).
RESULTS
Patients with FHONDA had a total of 15 different mutations in SLC38A8, of which 6 were novel. Excluding missing data, all patients had moderate to severe visual impairment (median visual acuity [VA] = 0.7 logMAR, interquartile range [IQR] = 0.6-0.8), nystagmus (28/28), and grade 4 foveal hypoplasia (17/17). Misrouting was present in all nine tested patients. None of the patients had any signs of hypopigmentation of skin and hair. VA in albinism was better (median = 0.5 logMAR, IQR = 0.3-0.7, P 0.006) and the phenotypes were more variable: 14 of 132 without nystagmus, foveal hypoplasia grades 1 to 4, and misrouting absent in 16 of 74.
CONCLUSIONS
Compared to albinism, the FHONDA syndrome appears to have a more narrow phenotypic spectrum, consisting of nonprogressive moderately to severely reduced VA, nystagmus, severe foveal hypoplasia, and misrouting. The co-occurrence of nystagmus, foveal hypoplasia, and misrouting in the absence of hypopigmentation implies that these abnormalities are not caused by lack of melanin, which has important implications for understanding the pathogenesis of these features.
Topics: Adolescent; Adult; Aged; Albinism, Oculocutaneous; Amino Acid Transport Systems, Neutral; Anterior Eye Segment; Child; Child, Preschool; DNA; DNA Mutational Analysis; Female; Follow-Up Studies; Fovea Centralis; Humans; Infant; Male; Middle Aged; Mutation; Phenotype; Retrospective Studies; Syndrome; Visual Acuity; Young Adult
PubMed: 35029636
DOI: 10.1167/iovs.63.1.19