Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex

Disrupted autophagy undermines skeletal muscle adaptation and integrity

This review assesses the importance of proteostasis in skeletal muscle maintenance with a specific emphasis on autophagy. Skeletal muscle appears to be particularly vulnerable to genetic defects in basal and induced autophagy, indicating that autophagy is co-substantial to skeletal muscle maintenance and adaptation. We discuss emerging evidence that tension-induced protein unfolding may act as a direct link between mechanical stress and autophagic pathways. Mechanistic links between protein damage, autophagy and muscle hypertrophy, which is also induced by mechanical stress, are still poorly understood. However, some mouse models of muscle disease show ameliorated symptoms upon effective targeting of basal autophagy. These findings highlight the importance of autophagy as therapeutic target and suggest that elucidating connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses is likely to reveal specific therapeutic windows for the treatment of muscle wasting disorders

Effect of habitat spatiotemporal structure on collembolan diversity

Landscape fragmentation is a major threat to biodiversity. It results in the transformation of continuous (hence large) habitat patches into isolated (hence smaller) patches, embedded in a matrix of another habitat type. Many populations are harmed by fragmentation because remnant patches do not fulfil their ecological and demographic requirements. In turn, this leads to a loss of biodiversity, especially if species have poor dispersal abilities. Moreover, landscape fragmentation is a dynamic process in which patches can be converted from one type of habitat to another. A recently created habitat might suffer from a reduced biodiversity because of the absence of adapted species that need a certain amount of time to colonize the new patch (e.g. direct meta-population effect). Thus landscape dynamics lead to complex habitat spatiotemporal structured, in which each patch is more or less continuous in space and time. In this study, we define habitat spatial structure as the degree to which a habitat is isolated from another habitat of the same kind and temporal structure as the time since the habitat is in place. Patches can also display reduced biodiversity because their spatial or temporal structures are correlated with habitat quality (e.g. indirect effects). We discriminated direct meta-community effects from indirect (habitat quality) effects of the spatiotemporal structure of habitats on biodiversity using Collembola as a model. We tested the relative importance of spatial and temporal structure of habitats for collembolan diversity, taking soil properties into account. In an agroforested landscape, we set up a sampling design comprised of two types of habitats (agriculture versus forest), a gradient of habitat isolation (three isolation classes) and two contrasting ages of habitats. Our results showed that habitat temporal structure is a key factor shaping collembolan diversity. A reduced diversity was detected in recent habitats, especially in forests. Interactions between temporal continuity and habitat quality were also detected by taking into account soil properties: diversity increased with soil carbon content, especially in old forests. Negative effects of habitat age on diversity were stronger in isolated patches. We conclude that habitat temporal structure is a key factor shaping collembolan diversity, while direction and amplitude of its effect depend on land use type and spatial isolation

Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function

Growth hormone (GH) exerts its actions via coordinated pulsatile secretion from a GH cell network into the bloodstream. Practically nothing is known about how the network receives its inputs in vivo and releases hormones into pituitary capillaries to shape GH pulses. Here we have developed in vivo approaches to measure local blood flow, oxygen partial pressure, and cell activity at single-cell resolution in mouse pituitary glands in situ. When secretagogue (GHRH) distribution was modeled with fluorescent markers injected into either the bloodstream or the nearby intercapillary space, a restricted distribution gradient evolved within the pituitary parenchyma. Injection of GHRH led to stimulation of both GH cell network activities and GH secretion, which was temporally associated with increases in blood flow rates and oxygen supply by capillaries, as well as oxygen consumption. Moreover, we observed a time-limiting step for hormone output at the perivascular level; macromolecules injected into the extracellular parenchyma moved rapidly to the perivascular space, but were then cleared more slowly in a size-dependent manner into capillary blood. Our findings suggest that GH pulse generation is not simply a GH cell network response, but is shaped by a tissue microenvironment context involving a functional association between the GH cell network activity and fluid microcirculation

794 Postzygotic dominant-negative mutations of RHOA cause a mosaic neuroectodermal syndrome

IF 6.448 (2017)International audienc