From disease modelling to personalised therapy in patients with CEP290 mutations

Molinari, Elisa; Srivastava, Shalabh; Sayer, John A.

doi:10.12688/f1000research.11553.1

Cited by 10 publications

(11 citation statements)

References 22 publications

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“…While restoration of developmental defects ( e.g ., skeletal anomalies) may only be possible at an early stage of human development, other phenotypic presentations, such as retinal degeneration or kidney function, may have a longer window of opportunity for intervention. Encouragingly, progress towards such therapies is being made: For example, “rescues” of mutations in the CEP290 gene, which encodes a TZ protein, have been demonstrated in a murine ciliopathy model, as well as in patient cells .…”

Section: Discussionmentioning

confidence: 99%

Role for intraflagellar transport in building a functional transition zone

Jensen

Lambacher

et al. 2018

EMBO Reports

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Genetic disorders caused by cilia dysfunction, termed ciliopathies, frequently involve the intraflagellar transport (IFT) system. Mutations in IFT subunits—including IFT‐dynein motor DYNC2H1—impair ciliary structures and Hedgehog signalling, typically leading to “skeletal” ciliopathies such as Jeune asphyxiating thoracic dystrophy. Intriguingly, IFT gene mutations also cause eye, kidney and brain ciliopathies often linked to defects in the transition zone (TZ), a ciliary gate implicated in Hedgehog signalling. Here, we identify a C. elegans temperature‐sensitive (ts) IFT‐dynein mutant (che‐3; human DYNC2H1) and use it to show a role for retrograde IFT in anterograde transport and ciliary maintenance. Unexpectedly, correct TZ assembly and gating function for periciliary proteins also require IFT‐dynein. Using the reversibility of the novel ts‐IFT‐dynein, we show that restoring IFT in adults (post‐developmentally) reverses defects in ciliary structure, TZ protein localisation and ciliary gating. Notably, this ability to reverse TZ defects declines as animals age. Together, our findings reveal a previously unknown role for IFT in TZ assembly in metazoans, providing new insights into the pathomechanism and potential phenotypic overlap between IFT‐ and TZ‐associated ciliopathies.

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Section: Discussionmentioning

confidence: 99%

Role for intraflagellar transport in building a functional transition zone

Jensen

Lambacher

et al. 2018

EMBO Reports

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“…There is hope therefore that these and other animal models of NPHP will provide valuable insights for future personalized medicine treatments of NPHP in affected patients ( 162 ). However, despite the great number of promising interventions that has arisen from preclinical studies, no clinical trials have yet been conducted to test their therapeutic potential in NPHP patients, most of whom eligible for treatment would be less than 18 years of age ( 125 ).…”

Section: Treatment Of Nphpmentioning

confidence: 99%

Many Genes—One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders

et al. 2018

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Nephronophthisis (NPHP) is a renal ciliopathy and an autosomal recessive cause of cystic kidney disease, renal fibrosis, and end-stage renal failure, affecting children and young adults. Molecular genetic studies have identified more than 20 genes underlying this disorder, whose protein products are all related to cilia, centrosome, or mitotic spindle function. In around 15% of cases, there are additional features of a ciliopathy syndrome, including retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. Alongside, gene identification has arisen molecular mechanistic insights into the disease pathogenesis. The genetic causes of NPHP are discussed in terms of how they help us to define treatable disease pathways including the cyclic adenosine monophosphate pathway, the mTOR pathway, Hedgehog signaling pathways, and DNA damage response pathways. While the underlying pathology of the many types of NPHP remains similar, the defined disease mechanisms are diverse, and a personalized medicine approach for therapy in NPHP patients is likely to be required.

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“…In the same terms, PC can also be applied for the calculation of carrier frequencies (CF) [16,19] of causal variants of non-related diseases in genes with a recessive inheritance pattern, as well as in the analysis of trios [18,19]. In more complex scenarios, where modifying and risk/protective variants may tune the effect of causal variants, the mutational landscape of a disease may help identifying: i) genetic pleiotropy together with causal variants in recessive forms [22], ii) digenic inheritance [23], or iii) disease-associated triallelic sites as in BBS [24].…”

Section: Introductionmentioning

confidence: 99%

Aggregated genomic data as cohort-specific allelic frequencies can boost variants and genes prioritization in non-solved cases of inherited retinal dystrophies

Iancu

Perea-Romero

Núñez‐Moreno

et al. 2022

Preprint

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BackgroundThe introduction of next-generation sequencing in the diagnosis of genetic diseases has increased the known repertoire of causal variants and genes involved, as well as the amount of genomic information produced, that is not always shared or reused.MethodsWe built an allelic frequency database for a heterogeneous cohort of genetic diseases to explore the aggregated genomic information and boost the diagnosis in inherited retinal dystrophies (IRD). We retrospectively selected 5683 index-cases with clinical exome available, 1766 with IRD, and the rest with diverse genetic diseases. In our IRD cohort, 46% of the patients do not have conclusive diagnosis at the time of writing. We calculated the specific allele-frequencies of the solved and non-solved IRD subcohorts and compared them with suitable pseudocontrols that were used to prioritize variants. In addition, we developed a method to highlight genes with more frequent pathogenic variants in non-solved IRD cases than in pseudocontrols weighted by the increment of benign variants in the same comparison. Our resource was also used to calculate the carrier frequency of deleterious variants in IRD genes.ResultsPrioritized variants were significantly enriched in deleterious variants in non-solved IRD cases but not in solved. Focusing on non-solved IRD cases, we prioritized variants with a significant increment of frequencies in cases compared to pseudocontrols. Among them, eight variants may contribute to explain the phenotype of 10 cases. Applied to variants of uncertain significance (VUS) monitored in our laboratory, we detected 11 more frequent in IRD than in pseudocontrols, and 10 of them were reclassified as likely-pathogenic according to ACMG guidelines. We also identified 18 genes with an accumulated pathogenicity in non-solved IRD samples for further studies that provided new insights in five cases. Most prevalent genes carrying pathogenic mutations are ABCA4 (∼7%) and USH2A (∼3%).ConclusionsA cohort-specific database of allele frequencies is able to diagnose cryptic non-solved IRD cases, reclassify VUS, propose candidate genes, and calculate CF on genes of interest. The database operates as an engine providing new hypotheses in non-solved cases as well as offering new resources for genetic counselling.

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From disease modelling to personalised therapy in patients with CEP290 mutations

Cited by 10 publications

References 22 publications

Role for intraflagellar transport in building a functional transition zone

Role for intraflagellar transport in building a functional transition zone

Many Genes—One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders

Aggregated genomic data as cohort-specific allelic frequencies can boost variants and genes prioritization in non-solved cases of inherited retinal dystrophies

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