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Molecular Vision 2022Familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND) are genetic disorders that can be caused by mutations in the gene and affect retinal vasculature...
PURPOSE
Familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND) are genetic disorders that can be caused by mutations in the gene and affect retinal vasculature growth and development. This study aimed to describe the copy number variations (CNVs) in the gene in Chinese FEVR families and the associated phenotypes.
METHODS
This study recruited 651 FEVR families. SeqCNV was used to analyze the CNVs in the families without mutations in known FEVR-associated genes. Multiplex ligation-dependent probe amplification and semiquantitative multiplex PCR were performed to verify the CNVs. The probands and family members underwent complete ocular examinations.
RESULTS
CNVs were identified in four patients from three unrelated families, accounting for 15% of the patients with mutations and 0.46% of the entire FEVR cohort. Exon 2 deletions were detected in two families, and whole gene deletion was identified in one family. The affected individuals were born blind with total retinal detachment.
CONCLUSIONS
The findings confirm that CNVs are a common mutation type. The CNV-associated phenotype is congenital blindness with total retinal detachment. Antenatal genetic analyses and fetal ultrasound can facilitate early diagnosis and interventions in patients with mutations.
Topics: China; DNA Copy Number Variations; Eye Proteins; Familial Exudative Vitreoretinopathies; Humans; Nerve Tissue Proteins; Pedigree; Retinal Degeneration; Retinal Detachment
PubMed: 35656167
DOI: No ID Found -
Gene Expression Patterns : GEP 2011The Norrie disease gene (Ndp) codes for a secreted protein, Norrin, that activates canonical Wnt signaling by binding to its receptor, Frizzled-4. This signaling system...
The Norrie disease gene (Ndp) codes for a secreted protein, Norrin, that activates canonical Wnt signaling by binding to its receptor, Frizzled-4. This signaling system is required for normal vascular development in the retina and for vascular survival in the cochlea. In mammals, the pattern of Ndp expression beyond the retina is poorly defined due to the low abundance of Norrin mRNA and protein. Here, we characterize Ndp expression during mouse development by studying a knock-in mouse that carries the coding sequence of human placental alkaline phosphatase (AP) inserted at the Ndp locus (Ndp(AP)). In the CNS, Ndp(AP) expression is apparent by E10.5 and is dynamic and complex. The anatomically delimited regions of Ndp(AP) expression observed prenatally in the CNS are replaced postnatally by widespread expression in astrocytes in the forebrain and midbrain, Bergman glia in the cerebellum, and Müller glia in the retina. In the developing and adult cochlea, Ndp(AP) expression is closely associated with two densely vascularized regions, the stria vascularis and a capillary plexus between the organ of Corti and the spiral ganglion. These observations suggest the possibility that Norrin may have developmental and/or homeostatic functions beyond the retina and cochlea.
Topics: Animals; Brain; Ear; Embryo, Mammalian; Eye; Eye Proteins; Female; Male; Mice; Nerve Tissue Proteins
PubMed: 21055480
DOI: 10.1016/j.gep.2010.10.007 -
The Annals of Otology, Rhinology, and... Jul 2005Norrie disease is an X-linked recessive disorder in which patients are born blind and develop sensory hearing loss in adolescence. The hearing loss associated with...
OBJECTIVES
Norrie disease is an X-linked recessive disorder in which patients are born blind and develop sensory hearing loss in adolescence. The hearing loss associated with Norrie disease has been shown in a genetically altered knockout mouse to involve dysfunction of the stria vascularis; most other structures are preserved until the later stages of the disease. The objective of this study was to characterize the audiologic phenotype of Norrie disease for comparison with the pathophysiologic mechanism.
METHODS
The design combined two series of clinical audiologic evaluations, with special attention to speech intelligibility.
RESULTS
The audiologic results for 12 affected individuals and 10 carriers show that patients with Norrie disease retain high speech intelligibility scores even when the threshold loss is severe.
CONCLUSIONS
The cochlear mechanism-- failure of the stria vascularis-- accounts for some of the higher values in the wide distribution of speech scores in cases with similar pure tone audiograms.
Topics: Adult; Audiometry, Pure-Tone; Auditory Threshold; Blindness; Child; Cochlea; Cochlear Diseases; Female; Hearing Loss, Sensorineural; Humans; Male; Speech Intelligibility
PubMed: 16134349
DOI: 10.1177/000348940511400707 -
Genes Mar 2022While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than...
While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than retinitis pigmentosa. We wanted to determine if multigenic protein-altering variants are common in FEVR subjects within a set of FEVR-related genes. The potential occurrence of protein-altering variants in two different genes has been documented in a very small percentage of patients, but potential multigenic contributions to FEVR remain unclear. Genes involved in these orphan pediatric retinal diseases are not universally included in available IRD targeted-sequencing panels, and cost is also a factor limiting multigenic-sequence-based testing for these rare conditions. To provide an accurate solution at lower cost, we developed a targeted-sequencing protocol that includes seven genes involved in Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie disease. Seventy-six DNA samples from persons refered to clinic with possible FEVR and some close relatives were sequenced using a novel Oakland-ERI orphan pediatric retinal disease panel (version 2) providing 900 times average read coverage. The seven genes involved in FEVR/ND were: (ChrX), (Chr3); (Chr7); (Chr10), (Chr11), (Chr11), (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: 13/33 (40%), 9/33 (27%), 6/33 (18%), ( 3/33 (9%), 1/33 (3%), 1/33 (3%). Most protein-altering variants, 85%, were found in three genes: , , and . Four previously known pathogenic variants were detected in five families and two unrelated individuals. Two novel, likely pathogenic variants were detected in one family (FZD4: Cys450ter), and a likely pathogenic frame shift termination variant was detected in one unrelated individual (LRP5: Ala919CysfsTer67). The average number of genes with protein-altering variants was greater in subjects with confirmed FEVR (1.46, = 30) compared to subjects confirmed unaffected by FEVR (0.95, = 20), ( = 0.009). Thirty-four percent of persons sequenced had digenic and trigenic protein-altering variants within this set of FEVR genes, which was much greater than expected in the general population (3.6%), as derived from GnomAD data. While the potential contributions to FEVR are not known for most of the variants in a multigenic context, the high multigenic frequency suggests that potential multigenic contributions to FEVR severity warrant future investigation. The targeted-sequencing format developed will support such exploration by reducing the testing cost to $250 (US) for seven genes and facilitating greater access to genetic testing for families with this very rare inherited retinal disease.
Topics: Blindness; Child; DNA Mutational Analysis; DNA-Binding Proteins; Familial Exudative Vitreoretinopathies; Frizzled Receptors; Genetic Diseases, X-Linked; Humans; Low Density Lipoprotein Receptor-Related Protein-5; Mutation; Nervous System Diseases; Retinal Degeneration; Retinal Diseases; Spasms, Infantile; Tetraspanins; Transcription Factors
PubMed: 35328049
DOI: 10.3390/genes13030495 -
Investigative Ophthalmology & Visual... May 2023Familial exudative vitreoretinopathy (FEVR) and Norrie disease are examples of genetic disorders in which the retinal vasculature fails to fully form (hypovascular),...
PURPOSE
Familial exudative vitreoretinopathy (FEVR) and Norrie disease are examples of genetic disorders in which the retinal vasculature fails to fully form (hypovascular), leading to congenital blindness. While studying the role of a factor expressed during retinal development, T-box factor Tbx3, we discovered that optic cup loss of Tbx3 caused the retina to become hypovascular. The purpose of this study was to characterize how loss of Tbx3 affects retinal vasculature formation.
METHODS
Conditional removal of Tbx3 from both retinal progenitors and astrocytes was done using the optic cup-Cre recombinase driver BAC-Dkk3-Cre and was analyzed using standard immunohistochemical techniques.
RESULTS
With Tbx3 loss, the retinas were hypovascular, as seen in patients with retinopathy of prematurity (ROP) and FEVR. Retinal vasculature failed to form the stereotypic tri-layered plexus in the dorsal-temporal region. Astrocyte precursors were reduced in number and failed to form a lattice at the dorsal-temporal edge. We next examined retinal ganglion cells, as they have been shown to play a critical role in retinal angiogenesis. We found that melanopsin expression and Islet1/2-positive retinal ganglion cells were reduced in the dorsal half of the retina. In previous studies, the loss of melanopsin has been linked to hyaloid vessel persistence, which we also observed in the Tbx3 conditional knockout (cKO) retinas, as well as in infants with ROP or FEVR.
CONCLUSIONS
To the best of our knowledge, these studies are the first demonstration that Tbx3 is required for normal mammalian eye formation. Together, the results provide a potential genetic model for retinal hypovascular diseases.
Topics: Mice; Animals; Infant, Newborn; Humans; Retina; Retinal Degeneration; Retinal Ganglion Cells; Retinopathy of Prematurity; Retinal Vessels; Familial Exudative Vitreoretinopathies; Mammals; T-Box Domain Proteins
PubMed: 37126314
DOI: 10.1167/iovs.64.5.1 -
PloS One 2017Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and...
Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.
Topics: Angiography; Animals; Blindness; Capillaries; Cell Hypoxia; Disease Models, Animal; Disease Progression; Electroretinography; Eye Proteins; Genetic Diseases, X-Linked; Lasers; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Nerve Tissue Proteins; Nervous System Diseases; Ophthalmoscopy; Retinal Degeneration; Retinal Vessels; Spasms, Infantile
PubMed: 28575130
DOI: 10.1371/journal.pone.0178753 -
BMC Ophthalmology Feb 2021This study aims to analyze the Norrie disease gene (NDP) variants in patients with familial exudative vitreoretinopathy (FEVR) and their clinical features.
PURPOSE
This study aims to analyze the Norrie disease gene (NDP) variants in patients with familial exudative vitreoretinopathy (FEVR) and their clinical features.
METHODS
Thirty-three Chinese patients (22 familial and 11 simplex) who were diagnosed as FEVR underwent detailed ocular examinations in Beijing Tongren Hospital. Peripheral venous blood was drawn from the patients and their family members for the extraction of genomic DNA. All exons of NDP gene were analyzed by direct sequencing of PCR-amplified DNA fragments.
RESULTS
Four novel mutations in NDP gene were identified in four X-linked FEVR families: a C → T transversion, c. 625C → T, in exon 3, resulting in a serine-to-proline change in codon 73 (S73P); a C → G transition, c. 751C → G, in exon 3, resulting in an arginine-to-glycine change in codon 115 (R115G); a T → C transversion of nucleotide 331 at 5'UTR in exon 2 (c.331 T → C); and a C → T transversion of the nucleotide 5 in intron 1 (IVS1 + 5C → T). The mutations were not present in the control group (n = 100).
CONCLUSIONS
Our results extend the spectrum of NDP gene mutations. The mutations in the non-coding region of NDP may play a crucial role in the pathogenesis of FEVR.
Topics: Blindness; China; DNA Mutational Analysis; Eye Proteins; Familial Exudative Vitreoretinopathies; Genetic Diseases, X-Linked; Humans; Mutation; Nerve Tissue Proteins; Nervous System Diseases; Pedigree; Retinal Degeneration; Retinal Diseases; Spasms, Infantile
PubMed: 33588793
DOI: 10.1186/s12886-021-01852-3 -
Journal of Cell Science May 2013Mammalian LGR4, 5 and 6 are seven-transmembrane receptors that are important for diverse physiological processes. These receptors are orthologous to DLGR2, a Drosophila...
Mammalian LGR4, 5 and 6 are seven-transmembrane receptors that are important for diverse physiological processes. These receptors are orthologous to DLGR2, a Drosophila receptor activated by the burs/pburs heterodimer important for morphogenesis. Although recent studies indicated that four R-spondin proteins are cognate ligands for LGR4, 5 and 6 receptors, several BMP antagonists in vertebrates have been postulated to be orthologous to burs and pburs. Using newly available genome sequences, we showed that norrin is a vertebrate ortholog for insect burs and pburs and stimulates Wnt signaling mediated by LGR4, but not by LGR5 and 6, in mammalian cells. Although norrin could only activate LGR4, binding studies suggested interactions between norrin and LGR4, 5 and 6. Norrin, the Norrie disease gene product, is also capable of activating Wnt signaling mediated by the Frizzled4 receptor and serves as a BMP antagonist. Mutagenesis studies indicated that different norrin mutations found in patients with Norrie disease can be categorized into subgroups according to defects for signaling through the three distinct binding proteins. Thus, norrin is a rare ligand capable of binding three receptors/binding proteins that are important for BMP and Wnt signaling pathways.
Topics: Animals; Chickens; Drosophila Proteins; Drosophila melanogaster; Eye Proteins; Frizzled Receptors; Humans; Mice; Nerve Tissue Proteins; Receptors, G-Protein-Coupled; Wnt Signaling Pathway; Xenopus
PubMed: 23444378
DOI: 10.1242/jcs.123471 -
Journal of Genetics Dec 2017Contiguous microdeletions of the Norrie disease pseudoglioma (NDP) region on chromosome Xp11.3 have been widely confirmed as contributing to the typical clinical...
Contiguous microdeletions of the Norrie disease pseudoglioma (NDP) region on chromosome Xp11.3 have been widely confirmed as contributing to the typical clinical features of Norrie disease (ND). However, the precise relation between genotype and phenotype could vary. The contiguous deletion of NDP and its neighbouring genes, MAOA/B and EFHC2, reportedly leads to syndromic clinical features such as microcephaly, intellectual disability, and epilepsy. Herewe report a novel contiguous microdeletion of the NDP region containing the MAOB and EFHC2 genes,which causes eye defects but no cognitive disability.We detected a deletion of 494.6 kb atXp11.3 in both the proband and carrier mother. This deletionwas then used as the molecular marker in prenatal diagnosis for two subsequent pregnancies. The deletion was absent in one of the foetuses, who remain without any abnormalities at 2 years of age. The proband shows the typical ocular clinical features of ND including bilateral retinal detachment, microphthalmia, atrophic irides, corneal opacification, and cataracts, but no symptoms of microcephaly, intellectual disability, and epilepsy. This familial study demonstrates that a deficiency in one of two MAO genes may not lead to psychomotor delay, and deletion of EFHC2 may not cause epilepsy. Our observations provide new information on the genotype-phenotype relations of MAOA/B and EFHC2 genes involved in the contiguous deletions of ND.
Topics: Adult; Blindness; Calcium-Binding Proteins; Child, Preschool; Chromosome Deletion; Eye Proteins; Female; Genetic Diseases, X-Linked; Genotype; Humans; Intellectual Disability; Male; Monoamine Oxidase; Nerve Tissue Proteins; Nervous System Diseases; Retinal Degeneration; Sequence Deletion; Spasms, Infantile
PubMed: 29321361
DOI: 10.1007/s12041-017-0869-5 -
Genome Biology and Evolution Jun 2014The cystine knot growth factor (CKGF) superfamily includes important secreted developmental regulators, including the families of transforming growth factor beta, nerve...
The cystine knot growth factor (CKGF) superfamily includes important secreted developmental regulators, including the families of transforming growth factor beta, nerve growth factor, platelet-derived growth factor, and the glycoprotein hormones (GPHs). The evolutionary origin of the GPHs and the related invertebrate bursicon hormone, and their characteristic receptors, contributes to an understanding of the endocrine system in metazoans. Using a sensitive search method with hidden Markov models, we identified homologs of the hormones and receptors, along with the closely related bone morphogenetic protein (BMP) antagonists in basal metazoans. In sponges and a comb jelly, cystine knot hormones (CKHs) with mixed features of GPHs, bursicon, and BMP antagonists were identified using primary sequence and phylogenetic analysis. Also, we identified potential receptors for these CKHs, leucine-rich repeat-containing G protein-coupled receptors (LGRs), in the same species. Cnidarians, such as the sea anemone, coral, and hydra, diverged later in metazoan evolution and appear to have duplicated and differentiated CKH-like peptides resulting in bursicon/GPH-like peptides and several BMP antagonists: Gremlin (Grem), sclerostin domain containing (SOSD), neuroblastoma suppressor of tumorigenicity 1 (NBL1), and Norrie disease protein. An expanded cnidarian LGR group also evolved, including receptors for GPH and bursicon. With the appearance of bilaterians, a separate GPH (thyrostimulin) along with bursicon and BMP antagonists were present. Synteny indicates that the GPHs, Grem, and SOSD have been maintained in a common gene neighborhood throughout much of metazoan evolution. The stable and highly conserved CKGFs are not identified in nonmetazoan organisms but are established with their receptors in the basal metazoans, becoming critical to growth, development, and regulation in all animals.
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Follicle Stimulating Hormone; Glycoproteins; Humans; Intercellular Signaling Peptides and Proteins; Invertebrate Hormones; Molecular Sequence Data; Phylogeny; Receptors, G-Protein-Coupled; Sequence Alignment
PubMed: 24904013
DOI: 10.1093/gbe/evu118