Molecular treatment options for patients carrying KIAA0586/TALPID3 variants

Variants in KIAA0586/TALPID3 are associated with the ciliopathy Joubert syndrome (JS), which is a genetically heterogeneous disorder. Mutations in more than 40 different genes were associated with JS, genes that are relevant to ciliary assembly, maintenance, or cellular signaling pathways during the development. Genetic variability suggests that gene- and/or mutation-independent treatment strategies could be beneficial to patients. Currently, targeted therapeutic options are not available. In this study, we present molecular treatment options for pathogenic KIAA0586/TALPID3 sequence alterations. We compared therapeutic efficacy and side effects using patient-derived fibroblasts from two siblings affected by JS. The patients harbored two compound heterozygous sequence alterations, a non-sense mutation (KIAA0586/TALPID3: c.2353C>T) in exon 18 and a deep-intronic mutation in intron 28 (KIAA0586/TALPID3: c.3990 + 3186G>A). The deep-intronic sequence alteration activates a cryptic exon that causes a frameshift and splicing defect. Both variants are predicted to potentially result in the premature termination of translation. The patient-derived fibroblasts exhibited reduced primary cilia length and altered distribution of PCM1. These cellular defects were responsive to treatments with RNA-based therapeutics and/or readthrough agents (RTAs). Our results highlight the potential of addressing mutations and molecular defects associated with KIAA0586/TALPID3 sequence alterations as future perspectives toward treatments of patients.

• Publication year

  2025

• Venue

  Molecular Therapy: Nucleic Acids

• Publication date

  2025-08-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.omtn.2025.102688PMID 40951761PMCID 12423346
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Pathogenic KIAA0586/TALPID3 variants are associated with defects in primary and motile cilia

  2024cited by this paper
• Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis

  2023cited by this paper
• Genotype–phenotype correlates in Joubert syndrome: A review

  2022cited by this paper
• Translational Read-Through Drugs (TRIDs) Are Able to Restore Protein Expression and Ciliogenesis in Fibroblasts of Patients with Retinitis Pigmentosa Caused by a Premature Termination Codon in FAM161A

  2022cited by this paper
• Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing

  2022cited by this paper
• Lipid Nanoparticles as Delivery Systems for RNA-Based Vaccines

  2021cited by this paper
• Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

  2021cited by this paper
• An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

  2021cited by this paper
• Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms

  2021cited by this paper
• Current and Future Treatments in Primary Ciliary Dyskinesia

  2021cited by this paper
• TALPID3 and ANKRD26 selectively orchestrate FBF1 localization and cilia gating

  2020cited by this paper
• Suppression of Nonsense Mutations by New Emerging Technologies

  2020cited by this paper
• Translational Read-Through Therapy of RPGR Nonsense Mutations

  2020cited by this paper
• Talpid3-Mediated Centrosome Integrity Restrains Neural Progenitor Delamination to Sustain Neurogenesis by Stabilizing Adherens Junctions.

  2020cited by this paper
• Centriolar satellites are required for efficient ciliogenesis and ciliary content regulation

  2019cited by this paper
• Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations

  2019cited by this paper
• Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation

  2019cited by this paper
• CEP120 interacts with C2CD3 and Talpid3 and is required for centriole appendage assembly and ciliogenesis

  2019cited by this paper
• A distal centriolar protein network controls organelle maturation and asymmetry

  2018cited by this paper
• The ciliopathy protein TALPID3/KIAA0586 acts upstream of Rab8 activation in zebrafish photoreceptor outer segment formation and maintenance

  2018cited by this paper
• Antisense Oligonucleotide-Based Splicing Correction in Individuals with Leber Congenital Amaurosis due to Compound Heterozygosity for the c.2991+1655A>G Mutation in CEP290

  2018cited by this paper
• Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models

  2018cited by this paper
• Searching the second hit in patients with inherited retinal dystrophies and monoallelic variants in ABCA4, USH2A and CEP290 by whole-gene targeted sequencing

  2018cited by this paper
• Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines

  2017cited by this paper
• Deep intronic mutations and human disease

  2017cited by this paper
• Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs)

  2016cited by this paper
• Gene editing of DNAH11 restores normal cilia motility in primary ciliary dyskinesia

  2016cited by this paper
• Tethering of an E3 ligase by PCM1 regulates the abundance of centrosomal KIAA0586/Talpid3 and promotes ciliogenesis

  2016cited by this paper
• Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

  2015cited by this paper
• TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

  2015cited by this paper
• KIAA0586 is Mutated in Joubert Syndrome

  2015cited by this paper
• Localizing the RPGR protein along the cilium: a new method to determine efficacies to treat RPGR mutations

  2015cited by this paper
• Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

  2015cited by this paper
• Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

  2015cited by this paper
• Joubert syndrome: genotyping a Northern European patient cohort

  2015cited by this paper
• The CP110-interacting proteins Talpid3 and Cep290 play overlapping and distinct roles in cilia assembly

  2014cited by this paper
• Ataluren treatment of patients with nonsense mutation dystrophinopathy

  2014cited by this paper
• Phosphorothioates, Essential Components of Therapeutic Oligonucleotides

  2014cited by this paper
• Talpid3-Binding Centrosomal Protein Cep120 Is Required for Centriole Duplication and Proliferation of Cerebellar Granule Neuron Progenitors

  2014cited by this paper
• Failure of centrosome migration causes a loss of motile cilia in talpid3 mutants

  2013cited by this paper
• Role of Pseudoexons and Pseudointrons in Human Cancer

  2013cited by this paper
• Ataluren as an agent for therapeutic nonsense suppression.

  2013cited by this paper
• Pharmaceutical therapies to recode nonsense mutations in inherited diseases.

  2012cited by this paper
• Gene therapeutic approach using mutation-adapted U1 snRNA to correct a RPGR splice defect in patient-derived cells.

  2011cited by this paper
• Targeted mutation of the talpid3 gene in zebrafish reveals its conserved requirement for ciliogenesis and Hedgehog signalling across the vertebrates

  2011cited by this paper
• Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease.

  2011cited by this paper
• Alternative splicing: role of pseudoexons in human disease and potential therapeutic strategies

  2010cited by this paper
• Aminoglycoside-induced mutation suppression (stop codon readthrough) as a therapeutic strategy for Duchenne muscular dystrophy

  2010cited by this paper
• Joubert Syndrome and related disorders

  2010cited by this paper
• Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling

  2010cited by this paper
• Ciliary Beating Recovery in Deficient Human Airway Epithelial Cells after Lentivirus Ex Vivo Gene Therapy

  2009cited by this paper
• CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium.

  2008cited by this paper
• Joubert syndrome (and related disorders) (OMIM 213300)

  2007cited by this paper
• Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results.

  2003cited by this paper
• Assembly of centrosomal proteins and microtubule organization depends on PCM-1

  2002cited by this paper
• Aminoglycoside suppression of a premature stop mutation in a Cftr–/– mouse carrying a human CFTR-G542X transgene

  2002cited by this paper
• Pharmacokinetic properties of 2'-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats.

  2001cited by this paper
• "Joubert Syndrome" Revisited: Key Ocular Motor Signs With Magnetic Resonance Imaging Correlation

  1997cited by this paper
• Binding, uptake, and intracellular trafficking of phosphorothioate-modified oligodeoxynucleotides.

  1995cited by this paper

• No citing papers are available for this paper.