Novel Insights Into the Phenotypical Spectrum of <i>KIF11</i>-Associated Retinopathy, Including a New Form of Retinal Ciliopathy

Birtel, Johannes; Gliem, Martin; Mangold, Elisabeth; Tebbe, Lars; Spier, Isabel; Müller, Philipp L.; Holz, Frank G.; Neuhaus, Christine; Wolfrum, Uwe; Bolz, Hanno J.; Issa, Peter Charbel

doi:10.1167/iovs.17-21679

Cited by 51 publications

(48 citation statements)

References 30 publications

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“…To date the relationship between IRAK4 and KIF11 has not been investigated mechanistically and evidence for a KIF11 function in cilia is limited. However, a recent study of inherited KIF11-associated retinopathies has provided some support for the idea the protein localizes to cilia, and that these diseases represent a class of ciliopathy (55). These relationships are worth further evaluation in the context of ADPKD; like cancer, a disease in which inflammation plays an important role in disease pathogenesis, among many other signaling commonalities (49,50,56).…”

Section: Discussionmentioning

confidence: 99%

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Kiseleva

Korobeynikov

Nikonova

et al. 2019

Clinical Cancer Research

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Purpose: For many tumors, signaling exchanges between cancer cells and other cells in their microenvironment influence overall tumor signaling. Some of these exchanges depend on expression of the primary cilium on nontransformed cell populations, as extracellular ligands including Sonic Hedgehog (SHH), PDGFRa, and others function through receptors spatially localized to cilia. Cell ciliation is regulated by proteins that are themselves therapeutic targets. We investigated whether kinase inhibitors of clinical interest influence ciliation and signaling by proteins with ciliary receptors in cancer and other cilia-relevant disorders, such as polycystic kidney disease (PKD).Experimental Design: We screened a library of clinical and preclinical kinase inhibitors, identifying drugs that either prevented or induced ciliary disassembly. Specific bioactive protein targets of the drugs were identified by mRNA depletion. Mechanism of action was defined, and activity of select compounds investigated.Results: We identified multiple kinase inhibitors not previously linked to control of ciliation, including sunitinib, erlotinib, and an inhibitor of the innate immune pathway kinase, IRAK4. For all compounds, activity was mediated through regulation of Aurora-A (AURKA) activity. Drugs targeting cilia influenced proximal cellular responses to SHH and PDGFRa. In vivo, sunitinib durably limited ciliation and ciliarelated biological activities in renal cells, renal carcinoma cells, and PKD cysts. Extended analysis of IRAK4 defined a subset of innate immune signaling effectors potently affecting ciliation.Conclusions: These results suggest a paradigm by which targeted drugs may have unexpected off-target effects in heterogeneous cell populations in vivo via control of a physical platform for receipt of extracellular ligands. Conception and design: A.A. Kiseleva, V.A. Korobeynikov, E.A. Golemis Development of methodology: V.A. Korobeynikov, P. Makhov Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.A. Kiseleva, V.A. Korobeynikov, A.S. Nikonova, P. Zhang, M.B. Einarson Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.A.

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Section: Discussionmentioning

confidence: 99%

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Kiseleva

Korobeynikov

Nikonova

et al. 2019

Clinical Cancer Research

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“…Mutations in KIF11 have been shown to cause familial exudative vitreoretinopathy associated with retinal detachment [27]. Birtel et al, revealed that KIF11 is important in both ocular development and the maintenance of retinal morphology and function and defects in this protein have been associated with retinal ciliopathy [28]. KIFs are motor proteins involved in the activities of the centrosome and spindle during mitosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential molecular targets associated with proliferative diabetic retinopathy

Shao

et al. 2020

BMC Ophthalmol

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Background: This study aimed to identify and evaluate potential molecular targets associated with the development of proliferative diabetic retinopathy (DR). Methods: The microarray dataset "GSE60436" generated from fibrovascular membranes (FVMs) associated with proliferative DR was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from the active FVMs and control or inactive FVMs and control were evaluated and co-DEGs were identified using VEEN analysis. Functional enrichment analysis, and protein-protein interactions (PPI) network and module analyses were performed on the upregulated and downregulated coDEGs. Finally, several predictions regarding microRNAs (miRNAs) and transcription factors (TFs) were made to construct a putative TF-miRNA-target network. Results: A total of 1475 co-DEGs were screened in active/inactive FVM samples, including 461 upregulated and 1014 downregulated genes, which were enriched for angiogenesis [Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A) and Placental Growth Factor (PGF)] and visual perception, respectively. In the case of the upregulated co-DEGs, Kinesin Family Member 11 (KIF11), and BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) exhibited the highest values in both the PPI network and module analyses, as well as the genes related to mitosis. In the case of downregulated co-DEGs, several G protein subunits, including G Protein Subunit Beta 3 (GNB3), exhibited the highest values in both the PPI network and module analyses. The genes identified in the module analysis were found to be from the signal transduction-related pathways. In addition, we were able to identify four miRNAs and five TFs, including miR-136 and miR-374. Conclusions: In brief, HIF1A, PGF, KIF11, G protein subunits, and miR-136, miR-374 may all be involved in angiogenesis, retinal endothelial cell proliferation, and visual signal transduction in proliferative DR. This study provides a number of novel insights that may aid the development of future studies dedicated to discovering novel therapeutic targets in proliferative DR.

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“…EG5 also has non-mitotic functions such as involvement in endothelial cell lineage proliferation, secretory protein trans portation, and protein translation [Bar- , 2011;Exertier et al, 2013;Wakana et al, 2013]. EG5 possibly also has a role in the cilia [Birtel et al, 2017]. Jones et al [2014] assessed 37 individuals with KIF11 mutations and found microcephaly, ocular abnormality, lymphedema, epilepsy, and cardiac anomaly as major clinical features.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation of KIF11 in a Child with 22q11.2 Deletion Syndrome Associated with MCLMR

et al. 2018

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Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR; OMIM 152950) is a rare autosomal dominantly inherited syndrome. Mutations in the kinesin family member 11 (KIF11) gene have been associated with this condition. Here, we report a de novo novel heterozygous missense mutation in exon 12 of the KIF11 gene [c.1402T>G; p.(Leu468Val)] in a boy with 22q11.2 microdeletion syndrome. His major features were microcephaly, ventricular septal defect, congenital lymphedema of the feet, and distinct facial appearance including upslanting palpebral fissures, a broad nose with rounded tip, anteverted nares, long philtrum with a thin upper lip, pointed chin, and prominent ears. His right eye was enucleated due to subretinal hemorrhage and retinal detachment at age 3 months. Lacunae of chorioretinal atrophy and the pale optic disc were present in the left eye. He also had a de novo 1.6-Mb microdeletion in the Di George/VCFS region of chromosome 22q11.2 in SNP array, which was confirmed by FISH analysis. In this study, for the first time, we describe the co-occurrence of a KIF11 mutation and 22q11.2 deletion syndrome in a patient with MCLMR.

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Novel Insights Into the Phenotypical Spectrum of KIF11-Associated Retinopathy, Including a New Form of Retinal Ciliopathy

Cited by 51 publications

References 30 publications

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Identification of potential molecular targets associated with proliferative diabetic retinopathy

A Novel Mutation of KIF11 in a Child with 22q11.2 Deletion Syndrome Associated with MCLMR

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