<i>MERTK</i>
 mutation update in inherited retinal diseases

Audo, Isabelle; Mohand‐Saïd, Saddek; Boulanger-Scemama, Élise; Zanlonghi, Xavier; Condroyer, Christel; Démontant, Vanessa; Boyard, Fiona; Arnaiz‐Villena, Antonio; Méjécase, Cécile; Shamieh, Said El; Sahel, José‐Alain; Zeitz, Christina

doi:10.1002/humu.23431

Cited by 50 publications

(50 citation statements)

References 81 publications

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“…Among the other inhibitor targets identified in this screen, mutations affecting MERTK have also been associated with inherited retinopathies, and defects in retinal phagocytosis (57). Furthermore, expression of MERTK is affected in retinal cells of patients with ciliopathies, although no role for MERTK has as yet been defined in maturation of the retinal pigment epithelium in these patients (58).…”

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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“…The involvement of phagocytosis in central nervous system diseases is, however, less explored. Mutations in MERTK lead to retinal diseases possibly linked to deficient phagocytosis of photoreceptors (130). Similarly, mutations in TREM2 or its bridge protein DAP12 are well known to cause defects in phagocytosis by osteoclasts, causing bone cysts and early dementia (Nasu-Hakola disease) (131).…”

Section: Lesson 10 Does Phagocytosis Execute Cell Death?mentioning

confidence: 99%

Microglial Corpse Clearance: Lessons From Macrophages

et al. 2020

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From development to aging and disease, the brain parenchyma is under the constant threat of debris accumulation, in the form of dead cells and protein aggregates. To prevent garbage buildup, the brain is equipped with efficient phagocytes: the microglia. Microglia are similar, but not identical to other tissue macrophages, and in this review, we will first summarize the differences in the origin, lineage and population maintenance of microglia and macrophages. Then, we will discuss several principles that govern macrophage phagocytosis of apoptotic cells (efferocytosis), including the existence of redundant recognition mechanisms ("find-me" and "eat-me") that lead to a tight coupling between apoptosis and phagocytosis. We will then describe that resulting from engulfment and degradation of apoptotic cargo, phagocytes undergo an epigenetic, transcriptional and metabolic rewiring that leads to trained immunity, and discuss its relevance for microglia and brain function. In summary, we will show that neuroimmunologists can learn many lessons from the well-developed field of macrophage phagocytosis biology.

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“…However, as both ␣V␤5 integrin and CD36 localize at the RPE soma (10,12), their participation in COS recognition and binding is unlikely. A recent large-cohort genetic study of inherited retina diseases found that MerTK mutations exist in a small percentage of CRD patients (40), suggesting a conserved MerTK-dependent mechanism between ROS and COS phagocytosis. In agreement with this, MerTK is expressed at apical RPE microvilli (38).…”

Section: Rab28 and Cone Dystrophymentioning

confidence: 99%

The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium

Ying

Boldt

Ueffing

et al. 2018

Journal of Biological Chemistry

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RAB28, a member of the RAS oncogene family, is a ubiquitous, farnesylated, small GTPase of unknown function present in photoreceptors and the retinal pigmented epithelium (RPE). Nonsense mutations of the human gene cause recessive cone-rod dystrophy 18 (CRD18), characterized by macular hyperpigmentation, progressive loss of visual acuity, RPE atrophy, and severely attenuated cone and rod electroretinography (ERG) responses. In an attempt to elucidate the disease-causing mechanism, we generated mice by deleting exon 3 and truncating RAB28 after exon 2. We found that mice recapitulate features of the human dystrophy ( they exhibited reduced cone and rod ERG responses and progressive retina degeneration). Cones of mice extended their outer segments (OSs) to the RPE apical processes and formed enlarged, balloon-like distal tips before undergoing degeneration. The visual pigment content of WT and cones was comparable before the onset of degeneration. Cone phagosomes were almost absent in mice, whereas rod phagosomes displayed normal levels. A protein-protein interaction screen identified several RAB28-interacting proteins, including the prenyl-binding protein phosphodiesterase 6 δ-subunit (PDE6D) and voltage-gated potassium channel subfamily J member 13 (KCNJ13) present in the RPE apical processes. Of note, the loss of PDE6D prevented delivery of RAB28 to OSs. Taken together, these findings reveal that RAB28 is required for shedding and phagocytosis of cone OS discs.

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MERTK mutation update in inherited retinal diseases

Cited by 50 publications

References 81 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

Microglial Corpse Clearance: Lessons From Macrophages

The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium

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