The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling DOI Creative Commons

Jessica Schäfer,

Nicole Wenck,

Katharina Janik

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Фев. 8, 2023

Human Usher syndrome (USH) is the most common form of hereditary combined deaf-blindness. USH a complex genetic disorder, and pathomechanisms underlying disease are far from being understood, especially in eye retina. The USH1C gene encodes scaffold protein harmonin which organizes networks due to binary interactions with other proteins, such as all proteins. Interestingly, only retina inner ear show disease-related phenotype, although /harmonin almost ubiquitously expressed human body upregulated colorectal cancer. We that binds β -catenin, key effector canonical Wnt (cWnt) signaling pathway. also demonstrate interaction stabilized acetylated nuclei. In HEK293T cells, overexpression significantly reduced cWnt signaling, but -R31* mutated did not. Concordantly, we observed an increase dermal fibroblasts derived R31*/R80Pfs*69 patient compared healthy donor cells. RNAseq analysis reveals both expression genes related pathway target were altered patient-derived Finally, was reverted fibroblast cells by application Ataluren, small molecule suitable induce translational read-through nonsense mutations, hereby restoring some expression. Our results phenotype establishing suppressor cWnt/ -catenin

Язык: Английский

Advances in gene therapy hold promise for treating hereditary hearing loss DOI Creative Commons

Luoying Jiang,

Daqi Wang,

Yingzi He

и другие.

Molecular Therapy, Год журнала: 2023, Номер 31(4), С. 934 - 950

Опубликована: Фев. 8, 2023

Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing reconstructing material, thus being expected be the most promising strategy for disorders. Due growing attention hearing impairment, an increasing amount of research is attempting utilize gene hereditary loss (HHL), important monogenic disease and common type congenital deafness. Several clinical trials HHL have recently been approved, and, additionally, CRISPR-Cas tools attempted treatment. Therefore, in order further advance development inner ear promote its broad application other forms disease, it imperative review progress HHL. Herein, we address three main strategies (gene replacement, suppression, editing), summarizing that appropriate particular based different pathogenic mechanisms, then focusing their successful applications preclinical trials. Finally, elaborate challenges outlooks

Язык: Английский

Процитировано

78
Types of Inheritance and Genes Associated with Familial Meniere Disease DOI Creative Commons
Alberto M. Parra-Pérez, José A. López‐Escámez

Journal of the Association for Research in Otolaryngology, Год журнала: 2023, Номер 24(3), С. 269 - 279

Опубликована: Апрель 6, 2023

Abstract Meniere disease (MD) is a rare disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes vertigo and tinnitus. The phenotype variable, it may be other comorbidities such as migraine, respiratory allergies, several autoimmune disorders. condition has significant heritability according to epidemiological familial segregation studies. Familial MD found in 10% cases, most frequently genes being OTOG , MYO7A TECTA previously autosomal dominant recessive non-syndromic SNHL. These findings suggest new hypothesis where proteins involved extracellular structures apical surface sensory epithelia (otolithic tectorial membranes) stereocilia links would key elements pathophysiology MD. ionic homeostasis otolithic membranes could critical suppress innate motility individual hair cell bundles. Initially, focal detachment these cause random depolarization cells will explain changes tinnitus loudness or trigger attacks early stages With progression disease, larger lead an membrane herniation into horizontal semicircular canal dissociation caloric head impulse responses. shows different types inheritance, including compound patterns implementation genetic testing improve our understanding structure

Язык: Английский

Процитировано

21
Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models DOI Open Access
Andrew McDonald, Jan Wijnholds

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2887 - 2887

Опубликована: Март 1, 2024

The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial can often lead to death the and loss vision. Retinal ciliopathies are genetically diverse range inherited retinal disorders affecting aspects Despite advances in understanding utilising animal disease models, they lack ability accurately mimic observed patient phenotype, possibly due structural functional deviations from retina. Human-induced pluripotent stem cells (hiPSCs) be utilised generate an alternative model, 3D organoid, which contains all major cell types including photoreceptors complete with structures. These organoids facilitate study mechanisms potential therapies human-derived system. Three-dimensional still developing technology, despite impressive progress, several limitations remain. This review will discuss state hiPSC-derived organoid technology for modelling prominent related genes, RPGR, CEP290, MYO7A, USH2A. Additionally, we development novel gene therapy approaches targeting ciliopathies, delivery large genes gene-editing techniques.

Язык: Английский

Процитировано

8
Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss DOI Creative Commons
Clara Mendia, Thibault Peineau, Mina Zamani

и другие.

Molecular Therapy, Год журнала: 2024, Номер 32(3), С. 800 - 817

Опубликована: Янв. 18, 2024

Hearing loss is a major health concern affecting millions of people worldwide with currently limited treatment options. In clarin-2-deficient Clrn2

Язык: Английский

Процитировано

7
Syndromic Retinitis Pigmentosa: A Narrative Review DOI Creative Commons

Márta Janáky,

Gábor Braunitzer

Vision, Год журнала: 2025, Номер 9(1), С. 7 - 7

Опубликована: Янв. 20, 2025

Retinitis pigmentosa (RP) encompasses inherited retinal dystrophies, appearing either as an isolated eye condition or part of a broader systemic syndrome, known syndromic RP. In these cases, RP includes symptoms impacting other organs, complicating diagnosis and management. This review highlights key syndromes linked with RP, such Usher, Bardet–Biedl, Alström syndromes, focusing on genetic mutations, inheritance, clinical symptoms. These insights support clinicians in recognizing early. Ocular signs like nystagmus congenital cataracts may indicate disease, prompting testing. Conversely, necessitate exams, even if vision are absent. Understanding the aspects emphasizes need for multidisciplinary collaboration among ophthalmologists, pediatricians, specialists to optimize patient care. The also addresses emerging therapies aimed at both visual symptoms, though more extensive studies required confirm their effectiveness. Overall, by detailing profiles this seeks aid healthcare professionals diagnosing managing complex conditions effectively, enhancing outcomes through timely, specialized intervention.

Язык: Английский

Процитировано

1
Latest trends & strategies in ocular drug delivery DOI

Nishant S. Kulkarni,

Alexander Josowitz,

Roshan James

и другие.

Methods, Год журнала: 2025, Номер 235, С. 100 - 117

Опубликована: Фев. 13, 2025

Язык: Английский

Процитировано

1
Myosin motors in sensory hair bundle assembly DOI Creative Commons
Zane G. Moreland, Jonathan E. Bird

Current Opinion in Cell Biology, Год журнала: 2022, Номер 79, С. 102132 - 102132

Опубликована: Окт. 17, 2022

Mechanosensory hair bundles are assembled from actin-based stereocilia that project the apical surface of cells in inner ear. Stereocilia architecture is critical for transduction sound and accelerations, structural defects these mechano-sensors a clinical cause hearing balance disorders humans. Unconventional myosin motors central to assembly shaping architecture. A sub-group with MyTH4-FERM domains (MYO7A, MYO15A) particularly important processes, hypothesized act as transporters delivering actin-regulatory cargos, addition generating force tension. In this review, we summarize existing evidence how MYO7A MYO15A operate their dysfunction leads pathology. We further highlight emerging properties MyTH4/FERM family speculate new functions might contribute towards acquisition maintenance mechano-sensitivity.

Язык: Английский

Процитировано

25
USH2A variants causing retinitis pigmentosa or Usher syndrome provoke differential retinal phenotypes in disease-specific organoids DOI Creative Commons
Carla Sanjurjo-Soriano,

Carla Jimenez-Medina,

Nejla Erkilic

и другие.

Human Genetics and Genomics Advances, Год журнала: 2023, Номер 4(4), С. 100229 - 100229

Опубликована: Авг. 7, 2023

There is an emblematic clinical and genetic heterogeneity associated with inherited retinal diseases (IRDs). The most common form retinitis pigmentosa (RP), a rod-cone dystrophy caused by pathogenic variants in over 80 different genes. Further complexifying diagnosis, individual RP genes can also alter the phenotype. USH2A prevalent gene for autosomal-recessive one of challenging because its large size and, hence, number variants. Moreover, give rise to non-syndromic syndromic RP, known as Usher syndrome (USH) type 2, which vision hearing loss. lack clear genotype-phenotype correlation or prognostic models renders diagnosis highly challenging. We report here long-awaited differential USH phenotype three human disease-specific models: fibroblasts, induced pluripotent stem cells (iPSCs), mature iPSC-derived organoids. we identified distinct phenotypes organoids from multiple individuals, were validated isogenic-corrected controls. Non-syndromic showed compromised photoreceptor differentiation, whereas striking unexpected cone Furthermore, complementary investigations macular atrophy high proportion compared further validating our observations that differentially affect cones. Overall, identification provides valuable robust readouts testing pathogenicity well efficacy therapeutic approaches cell types.

Язык: Английский

Процитировано

14
Biomolecular condensates and disease pathogenesis DOI
Ke Ruan, Ge Bai, Yanshan Fang

и другие.

Science China Life Sciences, Год журнала: 2024, Номер 67(9), С. 1792 - 1832

Опубликована: Июль 17, 2024

Язык: Английский

Процитировано

4
Bioinformatics characterization of variants of uncertain significance in pediatric sensorineural hearing loss DOI Creative Commons
Sloane Clay,

Adele K. Evans,

Regina M. Zambrano

и другие.

Frontiers in Pediatrics, Год журнала: 2024, Номер 12

Опубликована: Фев. 21, 2024

Introduction Rapid advancements in Next Generation Sequencing (NGS) and bioinformatics tools have allowed physicians to obtain genetic testing results a more rapid, cost-effective, comprehensive manner than ever before. Around 50% of pediatric sensorineural hearing loss (SNHL) cases are due etiology, thus regularly utilize targeted sequencing panels that identify variants genes related SNHL. These allow for early detection pathogenic which allows provide anticipatory guidance families. Molecular does not always reveal clear etiology the presence multigenic with varying classifications, including Variants Uncertain Significance (VUS). This study aims perform preliminary characterization patients associated Type II Usher Syndrome other variants. We also an interpretation algorithm reviewing molecular medical geneticists. Methods Review records and/or VUS identified several potential subjects interest. For purposes this study, two ADGRV1 compound heterozygotes met inclusion criteria. Sequencing, data processing, variant calling (the process by from sequence data) was performed at Invitae (San Francisco CA). The analysis followed recommendations outlined American College Medical Genetics Association Pathology (ACMG-AMP) 2015 2019. present utilizes computational analysis, predictive data, population as well clinical information chart review publicly available ClinVar database. Results Two were gene . Subject 1's predicted deleterious, while 2's non-deleterious. based on known ClinVar, multiple lines databases, presentation. Discussion Early diagnosis through NGS is ideal, families then able access wide range resources will ultimately support child their condition progresses. recommend build strong relationships geneticists carefully before making families, particularly when addressing VUS. Reclassification efforts supported studies like ours evidence or benign effects

Язык: Английский

Процитировано

3