Gain‐of‐function mutations in G‐protein–coupled receptor genes associated with human endocrine disorders

Fukami, Maki; Suzuki, Erina; Igarashi, Maki; Miyado, Mami; Ogata, Tsutomu

doi:10.1111/cen.13496

Cited by 21 publications

(18 citation statements)

References 43 publications

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“…This hypothesis is supported by evidence that treatment with melatonin during periods of light exposure is detrimental to long-term rod photoreceptor viability 8 . Dimerization of GPCR monomers (including MT1/MT2) is widely-considered to be essential to receptor functions 48 . Fukami et al 48,49 have proposed a paradoxical gain-of-function mechanism in which most WT GPCRs reside on the cell surface as homodimers or heterodimers under basal conditions, and that the presence of mutant/WT receptor dimers on the cell surface can negatively affect the activity and/ or cellular regulation of the WT dimer partners.…”

Section: Discussionmentioning

confidence: 99%

“…Dimerization of GPCR monomers (including MT1/MT2) is widely-considered to be essential to receptor functions 48 . Fukami et al 48,49 have proposed a paradoxical gain-of-function mechanism in which most WT GPCRs reside on the cell surface as homodimers or heterodimers under basal conditions, and that the presence of mutant/WT receptor dimers on the cell surface can negatively affect the activity and/ or cellular regulation of the WT dimer partners. The authors described a 'paradoxical' gain-of-function of the GPCR prokineticin receptor 2 (PROKR2) 49 .…”

Section: Discussionmentioning

confidence: 99%

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CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis

Wiechmann

Martin

Horb

2020

Sci Rep

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Nighttime surges in melatonin levels activate melatonin receptors, which synchronize cellular activities with the natural light/dark cycle. Melatonin receptors are expressed in several cell types in the retina, including the photon-sensitive rods and cones. Previous studies suggest that long-term photoreceptor survival and retinal health is in part reliant on melatonin orchestration of circadian homeostatic activities. This scenario would accordingly envisage that disruption of melatonin receptor signaling is detrimental to photoreceptor health. Using in vivo CRISPR/Cas9 genomic editing, we discovered that a small deletion mutation of the Mel1a melatonin receptor (mtnr1a) gene causes a loss of rod photoreceptors in retinas of developing Xenopus tropicalis heterozygous, but not homozygous mutant tadpoles. Cones were relatively spared from degeneration, and the rod loss phenotype was not obvious after metamorphosis. Localization of Mel1a receptor protein appeared to be about the same in wild type and mutant retinas, suggesting that the mutant protein is expressed at some level in mutant retinal cells. The severe impact on early rod photoreceptor viability may signify a previously underestimated critical role in circadian influences on long-term retinal health and preservation of sight. These data offer evidence that disturbance of homeostatic, circadian signaling, conveyed through a mutated melatonin receptor, is incompatible with rod photoreceptor survival. Circadian (daily) rhythms synchronize to the natural solar cycle via photoreceptive cells in the retina of the eye that detect radiant light energy and convey that information to inner retinal cells, some of which project to the brain. Cyclic oscillations of intracellular activity occur in many cells of the body, and are especially robust in retinal cells since they need to anticipate the 12 magnitudes in ambient light intensity changes that can occur over a 24-h period 1. The key circadian signaling molecule of darkness, melatonin, is produced by retinal photoreceptors at nighttime to drive circadian events in the eye and is secreted into the cerebrospinal fluid and general circulation from the pineal gland 2. Melatonin binds to integral membrane G protein-coupled receptors (GPCRs) expressed in target cells throughout the body to harmonize cellular activities with the predictable 24-h day/night cycle 3. Melatonin receptor subtypes are designated as Mel1a, Mel1b, and Mel1c in amphibians, fish and birds 4 , and as MT1, MT2, and GPR50 (which does not bind melatonin) in mammals, respectively 3. One primary function of melatonin in the retina is to enhance visual sensitivity to light at nighttime 5. If the solar light cycle is disengaged from circadian cellular readiness, the metabolic imbalance imposed on darkadapted photoreceptors by radiant light energy causes cell damage 6. The increased vulnerability of photoreceptors to light damage during subjective night 7 is consistent with reports that melatonin receptor activation exacerbates light-induced rod cell death...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis

Wiechmann

Martin

Horb

2020

Sci Rep

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“…A structural hypothesis on the effect of all SNVs located on ICL3 cannot be proposed at the moment giving the absence of a properly modeled domain. Solving the structure of GPR101 would constitute a great step toward a better understanding of the effects of its variants, especially since ICL3, where many of the variants are located, appears to be a hotspot for gain-offunction SNVs (Fukami et al 2018).…”

Section: Is Gpr101 Involved In Other Diseases?mentioning

confidence: 99%

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis

Trivellin

Faucz

Daly

et al. 2020

Endocrine-Related Cancer

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We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands.

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“…Anomalies in GPCRs caused by polymorphisms are associated with a variety of phenotypes and predisposition to certain diseases. It has been described more than 700 mutations that inactivate or over activate receptors, which are related to over 30 different human diseases ( Schöneberg et al, 2004 ; Zalewska et al, 2014 ; Fukami et al, 2018 ). Marott, Nordestgaard et al (2013) identified genetic variants of the AT1R in patients with atrial fibrillation (AF).…”

Section: Introductionmentioning

confidence: 99%

Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans

et al. 2020

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The AT1 receptor (AT1R) has a major role in the Renin-Angiotensin System, being involved in several physiological events including blood pressure control and electrolyte balance. The AT1R is a member of the G protein coupled receptors (GPCR) family, classically known to couple Gαq and engage β-arrestin recruitment. Both G protein and arrestin signaling pathways are involved in modulation of different downstream kinases. A previous study reported that mutations in the AT1R (A244S and I103T-A244S) were positively correlated with higher risk of atrial fibrillation in men. Based on that report, we aimed to investigate if these mutations, including I103T only, could affect AT1R signal transduction profile, and consequently, implicate in atrial fibrillation outcome. To address that, we engineered an AT1R carrying the above-mentioned mutations, and functionally evaluated different signaling pathways. Phosphokinase profiler array to assess the mutations downstream effects on kinases and kinase substrates phosphorylation levels was used. Our results show that the I103T-A244S mutant receptor presents decreased β-arrestin 2 recruitment, which could lead to a harmful condition of sustained Gαq signaling. Moreover, the phosphokinase profiler array revealed that the same mutation led to downstream modulation of kinase pathways that are linked to physiological responses such as fibrous tissue formation, apoptosis and cell proliferation.

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Gain‐of‐function mutations in G‐protein–coupled receptor genes associated with human endocrine disorders

Cited by 21 publications

References 43 publications

CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis

CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis

Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans

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