Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome

Zhang, April; Duchatelet, Sabine; Lakdawala, Nikita; Tower, Richard L.; Diamond, Carrie; Marathe, Kalyani; Hill, India; Richard, Gabriele; Diab, Yaser; Kirkorian, A. Yasmine; Watanabe, Flora; Siegel, Dawn H.; Hovnanian, Alain

doi:10.1001/jamadermatol.2019.4141

Cited by 31 publications

(26 citation statements)

References 15 publications

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“…TRPV3 is most abundantly expressed in skin keratinocytes and in cells surrounding hair follicles, where it plays an essential role in cutaneous sensation. RT-PCR or q-PCR analysis showing the absence of TRPV3 in human BMECs ( Golech et al, 2004 ; Hatano et al, 2013 ) and gain-of-function mutations in human TRPV3 are associated with Olmsted syndrome, which is characterized by severe palmoplantar and periorificial keratoderma ( Greco et al, 2020 ; Zhang et al, 2020 ). TRPV4 has been reported to be widely expressed throughout the brain including hippocampus, hypothalamus, cerebellum, lamina terminalis and optic chiasm, as well as a special enhanced expression in the olfactory placodes ( Mangos et al, 2007 ; Kauer and Gibson, 2009 ; Shibasaki et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

Luo

Saubaméa

Chasseigneaux

et al. 2020

Front. Cell Dev. Biol.

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Transient receptor potential vanilloid 1-4 (TRPV1-4) expression and functionality were investigated in brain microvessel endothelial cells (BMEC) forming the blood–brain barrier (BBB) from rat and human origins. In rat, Trpv1-4 were detected by qRT-PCR in the brain cortex, brain microvessels, and in primary cultures of brain microvessel endothelial cells [rat brain microvessel endothelial cells (rPBMEC)]. A similar Trpv1-4 expression profile in isolated brain microvessels and rPBMEC was found with the following order: Trpv4 > Trpv2 > Trpv3 > Trpv1 . In human, TRPV1-4 were detected in the BBB cell line human cerebral microvessel endothelial cells D3 cells (hCMEC/D3) and in primary cultures of BMEC isolated from human adult and children brain resections [human brain microvascular endothelial cells (hPBMEC)], showing a similar TRPV1-4 expression profile in both hCMEC/D3 cells and hPBMECs as follow: TRPV2 > > TRPV4 > TRPV1 > TRPV3 . Western blotting and immunofluorescence experiments confirmed that TRPV2 and TRPV4 are the most expressed TRPV isoforms in hCMEC/D3 cells with a clear staining at the plasma membrane. A fluorescent dye Fluo-4 AM ester was applied to record intracellular Ca 2+ levels. TRPV4 functional activity was demonstrated in mediating Ca 2+ influx under stimulation with the specific agonist GSK1016790A (ranging from 3 to 1000 nM, EC 50 of 16.2 ± 4.5 nM), which was inhibited by the specific TRPV4 antagonist, RN1734 (30 μM). In contrast, TRPV1 was slightly activated in hCMEC/D3 cells as shown by the weak Ca 2+ influx induced by capsaicin at a high concentration (3 μM), a highly potent and specific TRPV1 agonist. Heat-induced Ca 2+ influx was not altered by co-treatment with a selective potent TRPV1 antagonist capsazepine (20 μM), in agreement with the low expression of TRPV1 as assessed by qRT-PCR. Our present study reveals an interspecies difference between Rat and Human. Functional contributions of TRPV1-4 subtype expression were not identical in rat and human tissues reflective of BBB integrity. TRPV2 was predominant in the human whereas TRPV4 had a larger role in the rat. This interspecies difference from a gene expression point of view should be taken into consideration when modulators of TRPV2 or TRPV4 are investigated in rat models of brain disorders.

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Section: Discussionmentioning

confidence: 99%

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

Luo

Saubaméa

Chasseigneaux

et al. 2020

Front. Cell Dev. Biol.

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“…This led the authors to propose the use of the EGFR inhibitor, with the aim of breaking the vicious circle initiated by the specific constitutive activation of TRPV3 36. The interest of such an innovative therapeutic approach was confirmed in four new patients with Olmsted syndrome linked to TRPV3 mutations 37…”

Section: Resultsmentioning

confidence: 99%

“…36 The interest of such an innovative therapeutic approach was confirmed in four new patients with Olmsted syndrome linked to TRPV3 mutations. 37…”

Section: Drug Repositioningmentioning

confidence: 99%

Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature*

et al. 2020

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Summary Background No specific or curative therapy exists for hereditary palmoplantar keratoderma (hPPK), which can profoundly alter patient quality of life, leading sometimes to severe functional impairment and pain. The rarity and the aetiological diversity of this group of disorders can explain the difficulty in comparing the efficacy of available treatments. Objectives To review the different treatments tried in patients with hPPK since 2008, their efficacy and safety, with an evaluation of the various therapeutic modalities that can be used to treat hPPK. Methods We undertook a comprehensive review of the literature data published since 2008. Results Only a few case series and individual case reports were identified. Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms. Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance. New targeted treatments, according to the specific mechanisms of hPPK, appear promising for the future. Conclusions More studies using robust methodology and involving larger cohorts of well‐characterized patients (phenotype–genotype) are necessary and should be prioritized by structured networks, such as the European Network for Rare Skin Diseases (ERN‐Skin), with the aim of better management of patients with rare skin diseases.

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“…The therapeutic success of targeting the epidermal growth factor receptor (EGFR) in OS [ 27 , 86 ] supports a model in which EGFR stimulates keratinocyte differentiation into corneocytes. According to this concept, EGFR increases the activity of TRPV3, leading to influx of Ca 2+ from the extracellular space into the stratum granulosum.…”

Section: Introductionmentioning

confidence: 99%

Beyond Ca2+ signalling: the role of TRPV3 in the transport of NH4+

Liebe

Sponder

et al. 2021

Pflugers Arch - Eur J Physiol

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Mutations of TRPV3 lead to severe dermal hyperkeratosis in Olmsted syndrome, but whether the mutants are trafficked to the cell membrane or not is controversial. Even less is known about TRPV3 function in intestinal epithelia, although research on ruminants and pigs suggests an involvement in the uptake of NH4+. It was the purpose of this study to measure the permeability of the human homologue (hTRPV3) to NH4+, to localize hTRPV3 in human skin equivalents, and to investigate trafficking of the Olmsted mutant G573S. Immunoblotting and immunostaining verified the successful expression of hTRPV3 in HEK-293 cells and Xenopus oocytes with trafficking to the cell membrane. Human skin equivalents showed distinct staining of the apical membrane of the top layer of keratinocytes with cytosolic staining in the middle layers. Experiments with pH-sensitive microelectrodes on Xenopus oocytes demonstrated that acidification by NH4+ was significantly greater when hTRPV3 was expressed. Single-channel measurements showed larger conductances in overexpressing Xenopus oocytes than in controls. In whole-cell experiments on HEK-293 cells, both enantiomers of menthol stimulated influx of NH4+ in hTRPV3 expressing cells, but not in controls. Expression of the mutant G573S greatly reduced cell viability with partial rescue via ruthenium red. Immunofluorescence confirmed cytosolic expression, with membrane staining observed in a very small number of cells. We suggest that expression of TRPV3 by epithelia may have implications not just for Ca2+ signalling, but also for nitrogen metabolism. Models suggesting how influx of NH4+ via TRPV3 might stimulate skin cornification or intestinal NH4+ transport are discussed.

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Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome

Cited by 31 publications

References 15 publications

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature*

Beyond Ca2+ signalling: the role of TRPV3 in the transport of NH4+

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