Norrie Disease Research Articles

Investigating the Impact of Dimer Interface Mutations on Norrin's Secretion and Norrin/β-Catenin Pathway Activation.

This study aimed to investigate the impact of 21 NDP mutations located at the dimer interface, focusing on their potential effects on protein assembly, secretion efficiency, and activation of the Norrin/β-catenin signaling pathway. The expression level, secretion efficiency, and protein assembly of mutations were analyzed using Western blot. The Norrin/β-catenin signaling pathway activation ability after overexpression of mutants or supernatant incubation of mutant proteins was tested in HEK293STF cells. The mutant norrin and wild-type (WT) FZD4 were overexpressed in HeLa cells to observe their co-localization. Immunofluorescence staining was conducted in HeLa cells to analyze the subcellular localization of Norrin and the Retention Using Selective Hook (RUSH) assay was used to dynamically observe the secretion process of WT and mutant Norrin. Four mutants (A63S, E66K, H68P, and L103Q) exhibited no significant differences from WT in all evaluations. The other 17 mutants presented abnormalities, including inadequate protein assembly, reduced secretion, inability to bind to FZD4 on the cell membrane, and decreased capacity to activate Norrin/β-catenin signaling pathway. The RUSH assay revealed the delay in endoplasmic reticulum (ER) exit and impairment of Golgi transport. Mutations at the Norrin dimer interface may lead to abnormal protein assembly, inability to bind to FZD4, and decreased secretion, thus contributing to compromised Norrin/β-catenin signaling. Our results shed light on the pathogenic mechanisms behind a significant proportion of NDP gene mutations in familial exudative vitreoretinopathy (FEVR) or Norrie disease.

Familial Exudative Vitreoretinopathy With and Without Pathogenic Variants of Norrin/β-Catenin Signaling Genes

PurposeTo determine the clinical characteristics of familial exudative vitreoretinopathy (FEVR) associated with or without pathogenic variants of the Norrin/β-catenin genes. DesignThis was a multicenter, cross-sectional, observational, and genetic study. SubjectsTwo-hundred eighty-one probands with FEVR were studied. MethodsWhole exome sequence and/or Sanger sequence was performed for the Norrin/β-catenin genes, the FZD4, LRP5, TSPAN12 and NDP genes on blood collected from the probands. The clinical symptoms of the probands with or without the pathogenic variants were assessed as well as differences in the inter Norrin/β-catenin genes. ResultsOne-hundred eight probands (38.4%) had 88 different pathogenic or likely pathogenic variants in the genes: 24 with the FZD4, 42 with the LRP5, 10 with the TSPAN12, and 12 with the NDP gene. Compared with the 173 probands without pathogenic variants, the 108 variant-positive probands had characteristics of familial predisposition (63.9% vs 37.6%, P <0.0001), progression during infancy (75.0% vs 53.8%, P = 0.0004), asymmetrical severity between the two eyes (50.0% vs 37.6%, P = 0.0472), and non-syndromic characteristics (10.2% vs 17.30%, P = 0.1185). The most frequent stage at which the more severe eye conditions was present was at Stage 4 in both groups (40.7% vs 34.7%). However, the advanced Stages of 3 to 5 in the more severe eye was found more frequently in probands with variants than in those without variants (83.3% vs 58.4%, P <0.0001). Patients with rhegmatogenous retinal detachments progressed from Stage 1 or 2 were found less frequently in the variant-positive probands (8.3% vs 17.3%, P = 0.0346). Eight probands with NDP variants had features different from probands with typical Norrin/β-catenin gene variants including the sporadic, symmetrical, and systemic characteristics consistent with Norrie disease. ConclusionsThe results showed that the clinical characteristics of FEVR of patients with variants in the Norrin/β-catenin genes are different from those with other etiologies. We recommend that clinicians who diagnose a child with FEVR perform genetic testing so that the parents can be informed on the prognosis of the vision and general health in the child.

Novel mutation in the NDP gene associated with Norrie disease in a Chinese pedigree.

Norrie disease (ND) is a rare X-linked recessive disorder characteristic of early childhood blindness. While several mutations in the NDP gene have been reported as causative for ND, the genetic etiology remains unknown for many patients. This study aims to describe a novel mutation and explore the clinical manifestations in a Chinese family with two affected males. Exome sequencing (ES) was employed to identify the causative gene in a four-generation pedigree. Sanger sequencing was subsequently utilized to validate the mutation detected by ES in additional family members. Ophthalmologic examination and diagnostic imaging relevant to ND were conducted. The proband (IV:2), an 8-month-old male infant, presented with binocular retinal detachment. DNA sequencing revealed a novel heterozygous missense mutation (c.174G>C) within the NDP gene in the proband. This mutation affected highly conserved residues and was predicted to disrupt the normal protein structure. Furthermore, the variant co-segregated with the disease phenotypes within the family. Our findings identified a novel missense mutation in the NDP gene associated with Norrie disease in China, expanding the mutation spectrum associated with ND. This discovery holds diagnostic, prognostic, and genetic counseling implications for affected individuals.

Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome.

Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function, and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway, such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goal of this review is to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.

49 Case Study: Cognitive Deficits Associated with Norrie Disease

Objective:Norrie disease is a rare, x-linked recessive genetic disorder associated with an NDP gene mutation. Males are predominantly affected. Typical symptoms include vision loss around the time of birth and progressive hearing loss. Cognitive and behavioral abnormalities also occur in 30-50% of individuals, including developmental delays, intellectual disability, cognitive regression, psychosis, and aggression. There is limited research, however, examining the neuropsychological deficits in adulthood resulting from Norrie disease, especially with neuropsychological data and in individuals without other neurological manifestations of the disease, such as seizures. Here, we present the neurocognitive profile of a patient with Norrie disease who presented for a cognitive evaluation in adulthood due to report of more recent memory decline.Participants and Methods:Mr. Smith is a Caucasian male in his mid-40's who previously underwent genetic testing and was subsequently diagnosed with Norrie disease. As a result of his diagnosis, he experienced complete vision loss since birth and bilateral hearing loss that began in childhood and gradually worsened in adolescence. Medical history was otherwise unremarkable. Developmental milestones were met on time. Historical intelligence testing conducted in elementary school revealed borderline on one intelligence test to high average performance on other intelligence tests. However, he was retained grades several times due to factors such as behavioral disruptions and academic difficulties. He had been employed as an assembly line worker for many years, but had not worked for 10 years prior to the neuropsychological evaluation. Emotionally, he had a longstanding history of anxiety and endorsed mild anxiety and depression at the time of the evaluation. The patient first noticed memory difficulties in adolescence then noticed further decline four years prior to the neuropsychological evaluation (around when he received a left-ear cochlear implant), which had remained stable since onset.Results:In the context of low average premorbid intellectual functioning, Mr. Smith's neurocognitive profile was notable for difficulties with alphanumeric set-shifting and abstract thinking, with otherwise preserved cognitive functioning. Weaknesses observed on testing may have represented longstanding weaknesses and did not rise to the level of a cognitive disorder. Affective distress was also suspected to have accounted for some of the cognitive lapses the patient reported experiencing with day-to-day functioning.Conclusions:The current poster aims to contribute to the limited body of literature examining neuropsychological deficits in adulthood resulting from Norrie disease. This is especially critical given that the long-term cognitive dysfunction of this disorder is relatively unknown and could negatively impact patients' quality of life over time.

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease.

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

Incontinentia Pigmenti and Norrie Disease: Pathogenesis, Diagnosis, and Treatment

Incontinentia pigmenti is a very rare X-linked dominant inherited disease characterized by skin lesions, retinal pathologies, central nervous system anomalies, and dental problems. Norrie disease is a very rare X-linked recessive inherited disease characterized by severe vitreoretinal dysplasia in both eyes at birth. In both diseases, patients can apply to the clinic with nystagmus, leukocoria, microphthalmia, and retinal detachment at an early age. In this review, Incontinentia pigmenti and Norrie disease, which are pediatric retinal vascular diseases, are investigated in detail.

Loss ofTbx3in Mouse Eye Causes Retinal Angiogenesis Defects Reminiscent of Human Disease

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. 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. 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. 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.

A Case Report of Norrie Disease with Congenital Sensorineural Hearing Loss

Norrie Disease (ND) is a rare X-linked recessive genetic disorder caused by mutations in the Norrie disease protein (NDP) gene on the X chromosome. This disorder leads to congenital or neonatal blindness, progressive hearing loss in adolescence, and cognitive or behavioral problems. Although hearing loss is a characteristic feature of ND, it is often overlooked due to the prominence of ocular symptoms. This article presents a rare case of ND in a 3-month-old boy who failed the universal newborn hearing screening (UNHS) bilaterally, further audiological evaluation revealed bilateral sensorineural hearing loss. Suggests that patients with ND may be born with congenital hearing loss, earlier than the previous reports. Addressing hearing loss at an early stage can help minimize the compounding effect on cognitive functioning and improve overall mental well-being.

Clinical Exome Sequencing Identifies NDP Gene Variants in Two Chinese Families with X-Linked Norrie Disease

Purpose: To explore the genetic defects in two Chinese families with X-linked Norrie disease (ND). Methods: We analyzed two Chinese families with ND at molecular level through clinical exome sequencing and the variations were identified by Sanger sequencing. Results: Two genetic variations were found in the NDP gene by clinical exome sequencing, a partial deletion of 801 bp contained the whole exon 2 and a missense variant (164G>A) within codon 55 that resulted in the interchange of cysteine by phenylalanine. Clinical findings were more severe in the patients who presented the missense variant. Conclusion: We report two genetic variations in the NDP gene in Chinese that extend the mutational and phenotypic spectra of NDP gene, and also demonstrate the feasibility of clinical exome sequencing in application of molecular diagnosis.

Ocular Manifestations in Patients with Sensorineural Hearing Loss.

Identification of ocular manifestations in patients with sensorineural hearing loss (SNHL) can have a large impact on the outcome and treatment of pediatric patients. Due to the common co-incidence of ocular manifestations and SNHL in children, both ophthalmologic and hearing loss screening and routine examinations must be conducted to minimize adverse outcomes and worsening of pathology. Early evaluation and diagnosis is imperative for intervention and further development of the patient. Co-incidence requires a thorough evaluation that includes a comprehensive history, examination, and diagnostic testing. In this article, a literature review was conducted to analyze the presentations of various diseases and syndromes, such as Alport Syndrome, Waardenburg Syndrome, Norrie Disease, Usher Disease, Stickler Syndrome, Marfan Syndrome, Congenital Rubella, and Hereditary Optic Neuropathies. We divided the various ocular pathologies into anterior and posterior segment presentations and associated systemic findings for better understanding. Additionally, this review aims to include an update on the management of patients with both ocular and hearing loss manifestations.

Next-generation sequencing reveals a case of Norrie disease in a child with bilateral ocular malformation.

A Norrie disease protein gene (NDP) variant, c.174 + 1G > A, was found in a Chinese family through next-generation sequencing and verified with Sanger sequencing. A case of Norrie disease was reported in the first child, and the symptoms were consistent with the results of gene sequencing. The child’s mother, who was pregnant at the time, was found to be a carrier of the identified pathogenic variant. To determine if the fetus carried the same disease-causing variant, prenatal examination and prenatal diagnosis were conducted. The fetus had biocular vitreous abnormalities and complete retinal abnormalities. Genetic testing showed that the fetus had maternally inherited the NDP gene variant found in the proband. It was concurrently confirmed that the NDP gene variant led to the deletion of 246 bp at the 3′ end of exon 2, resulting in the deletion of the initiation codon and the occurrence of disease. Our study suggests that the diagnosis of rare diseases through next-generation sequencing, combined with prenatal ultrasound and prenatal diagnosis, can help families with known familial genetic diseases. Furthermore, the findings of this study broaden the known genetic spectrum of Norrie disease.

Whole-genome sequencing revealed different demographic histories among the Korean endemic hill pigeon (Columba rupestris), rock pigeon (Columba livia var. domestica) and oriental turtle dove (Streptopelia orientalis).

The family Columbidae is known as the pigeon family and contains approximately 351 species and 50 genera. Compared to the wealth of biological and genomic information on these Columba livia var. domesteca, information on Columba rupestris and Streptopelia orientalis has been rather limited. The C. rupestris population size is decreasing in Korea. Whole-genome sequencing and identification of population characterization of each species based genome variation on 9 Korean pigeon and dove samples, namely, six hill pigeon (C. rupestris), one rock pigeon (C. livia var. domestica) and two oriental turtle dove (S. orientalis) samples. The whole genome of 9 genotypes were sequenced and mapped to the C. livia reference genome. Sequence alignment showed over 96% identity in C. rupestris and 94% identity in S. orientalis to the reference genome (GenBank assembly accession: GCA_001887795.1). Sequence variations, including single nucleotide polymorphisms (SNPs), insertions and deletions (InDels), and structural variations, revealed that intergenus (Columba vs. Streptopelia) variations were approximately four times higher than intragenus variations (C. livia vs. C. rupestris). Of the two Columba species, C. livia var. domestica is closer to S. orientalis than C. rupestris. Pairwise sequentially Markovian coalescent (PSMC) demographic history analysis revealed that the three species underwent a common population bottleneck between 105 and 120 Kya; since then, the effective population sizes of the rock pigeon and oriental turtle dove have increased. The effective population size of the hill pigeon, an Endangered Species of Grade II in Korea, has increased slowly from the second severe bottleneck that occurred approximately 0.5-1.4 × 104years ago. Our results showed no relationship between copy number variation in the Norrie disease protein (NDP) regulatory regions and plumage color patterns. We report the first comparative analysis of three pigeon genomes.

Long-Term Anatomic and Visual Outcomes of Planned Preterm Delivery and Treatment of Norrie Disease.

We previously reported that planned preterm delivery at 34 weeks gestational age provided an opportunity to treat Norrie disease in the vasoproliferative phase, prevented infantile retinal detachment, and preserved functional vision without further treatment after infancy. Although retinal vascularization did not proceed postnatally, after 8 years of follow-up, the retinas remained attached, and rudimentary foveal development was observed by optical coherence tomography. Best corrected visual acuity gradually improved to 20/80 with both eyes, and visual fields and real-world visual performance were remarkably functional. Global development progressed appropriately, and no long-term sequelae of premature delivery were observed. [Ophthalmic Surg Lasers Imaging Retina 2022;53:464-467.].

Spectrum of Mutations in NDP Resulting in Ocular Disease; a Systematic Review.

Aims and Rationale: The inner retina is supplied by three intraretinal capillary plexi whereas the outer retina is supplied by the choroidal circulation: NDP is essential for normal intraretinal vascularisation. Pathogenic variants in NDP (Xp11.3) may result in either a severe retinal phenotype associated with hearing loss (Norrie Disease) or a moderate retinal phenotype (Familial Exudative Vitreoretinopathy, FEVR). However, little is known about whether the nature or location of the NDP variant is predictive of severity. In this systematic review we summarise all reported NDP variants and draw conclusions about whether the nature of the NDP variant is predictive of the severity of the resulting ocular pathology and associated hearing loss and intellectual disability. Findings: 201 different variants in the NDP gene have been reported as disease-causing. The pathological phenotype that may result from a disease-causing NDP variant is quite diverse but generally comprises a consistent cluster of features (retinal hypovascularisation, exudation, persistent foetal vasculature, tractional/exudative retinal detachment, intellectual disability and hearing loss) that vary predictably with severity. Previous reviews have found no clear pattern in the nature of NDP mutations that cause either FEVR or Norrie disease, with the exception that mutations affecting cysteine residues have been associated with Norrie Disease and that visual loss amongst patients with Norrie disease tends to be more severe if the NDP mutation results in an early termination of translation as opposed to a missense related amino acid change. A key limitation of previous reviews has been variability in the case definition of Norrie disease and FEVR amongst authors. We thus reclassified patients into two groups based only on the severity of their retinal disease. Of the reported pathogenic variants that have been described in more than one patient, we found that any given variant caused an equivalent severity of retinopathy each time it was reported with very few exceptions. We therefore conclude that specific NDP mutations generally result in a consistent retinal phenotype each time they arise. Reports by different authors of the same variant causing either FEVR or Norrie disease conflict primarily due to variability in the authors’ respective case definitions rather than true differences in disease severity.

Endolymphatic Hydrop Phenotype in Familial Norrie Disease Caused by Large Fragment Deletion of NDP.

Norrie disease (ND; OMIM 310600), a rare X-linked recessive genetic disorder, is characterized by congenital blindness and occasionally, sensorineural hearing loss, and developmental delay. The congenital blindness of ND patients is almost untreatable; thus, hearing is particularly important for them. However, the mechanism of hearing loss of ND patients is unclear, and no good treatment is available except wearing hearing-aid. Therefore, revealing the mechanism of hearing loss in ND patients and exploring effective treatment methods are greatly important. In addition, as a serious monogenic genetic disease, convenient gene identification method is important for ND patients and their family members, as well as prenatal diagnosis and preimplantation genetic diagnosis to block intergenerational transmission of pathogenic genes. In this study, a Norrie family with two male patients was reported. This pedigree was ND caused by large fragment deletion of NDP (norrin cystine knot growth factor NDP) gene. In addition to typical severe ophthalmologic and audiologic defects, the patients showed new pathological features of endolymphatic hydrops (EH), and they also showed acoustic nerves abnormal as described in a very recent report. PCR methods were developed to analyze and diagnose the variation of the family members. This study expands the understanding of the clinical manifestation and pathogenesis of ND and provides a new idea for the treatment of patients in this family and a convenient method for the genetic screen for this ND family.

Epilepsy in Norrie disease

The insight into the Norrie disease viewed from neurology perspective and clinical case of refractory epilepsy relevant to the disease are considered. Epilepsy rarely accompanies Norrie disease. The dynamics of changes in electroencephalograms (EEG) and types of epileptic seizures during the disease progression as well as depending on the therapy received in the clinical case is analyzed. It is relevant for patients with Norrie disease to regularly undergo video-EEG monitoring to detect epileptiform activity, ictal patterns for timely diagnostics of epilepsy followed by prescribing proper therapy to improve quality of life.

NDP-related retinopathies: clinical phenotype of female carriers

Background/aimsNorrin cysteine knot growth factor (NDP) located on the X chromosome, was previously reported to cause Norrie disease and familial exudative vitreoretinopathy (FEVR), which are blindness-causing ocular disorders, in males....

A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes.

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: NDP (ChrX), CTNNB1 (Chr3); TSPAN12 (Chr7); KIF11 (Chr10), FZD4 (Chr11), LRP5 (Chr11), ZNF408 (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: LRP5 13/33 (40%), FZD4 9/33 (27%), ZNF408 6/33 (18%), (KIF11 3/33 (9%), NDP 1/33 (3%), CTNNB1 1/33 (3%). Most protein-altering variants, 85%, were found in three genes: FZD4, LRP5, and ZNF408. 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, n = 30) compared to subjects confirmed unaffected by FEVR (0.95, n = 20), (p = 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.

Hearing Function, Degeneration, and Disease: Spotlight on the Stria Vascularis.

The stria vascularis (SV) is a highly vascularized tissue lining the lateral wall of the cochlea. The SV maintains cochlear fluid homeostasis, generating the endocochlear potential that is required for sound transduction. In addition, the SV acts as an important blood-labyrinth barrier, tightly regulating the passage of molecules from the blood into the cochlea. A healthy SV is therefore vital for hearing function. Degeneration of the SV is a leading cause of age-related hearing loss, and has been associated with several hearing disorders, including Norrie disease, Meniere’s disease, Alport syndrome, Waardenburg syndrome, and Cytomegalovirus-induced hearing loss. Despite the SV’s important role in hearing, there is still much that remains to be discovered, including cell-specific function within the SV, mechanisms of SV degeneration, and potential protective or regenerative therapies. In this review, we discuss recent discoveries elucidating the molecular regulatory networks of SV function, mechanisms underlying degeneration of the SV, and otoprotective strategies for preventing drug-induced SV damage. We also highlight recent clinical developments for treating SV-related hearing loss and discuss future research trajectories in the field.