Inherited renal tubular dysgenesis: the first patients surviving the neonatal period

Renal tubular dysgenesis (RTD) is a clinical disorder either acquired during fetal development or inherited as an autosomal recessive condition. Inherited RTD is caused by mutations in the genes encoding the components of the renin-angiotensin system angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II receptor type 1. Inherited RTD is characterized by early onset oligohydramnios, skull ossification defects, preterm birth and neonatal pulmonary and renal failure. The histological hallmark is the absence or poor development of proximal tubules. So far, all patients died either in utero or shortly after birth. We report the first patients with inherited RTD surviving the neonatal period and still being alive. Genetic and functional analysis of the renin-angiotensin system contributes to the diagnosis of RTD. In conclusion, the clinical diagnosis of inherited RTD is easily missed after birth without renal biopsy or information on affected family members. Genetic and functional analysis of the renin-angiotensin system contributes to correct diagnosis

TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

Cellular transformation into myofibroblasts is a central physiological process enabling tissue repair. Its deregulation promotes fibrosis and carcinogenesis. TGF-β is the main inducer of the contractile gene program that drives myofibroblast differentiation from various precursor cell types. Crucial regulators of this transcriptional program are serum response factor (SRF) and its cofactor MKL1 (also known as MRTF-A). However, the exact mechanism of the crosstalk between TGF-β signaling and MKL1 remains unclear. Here, we report the discovery of a novel MKL1 variant/isoform, MKL1_S, transcribed from an alternative promoter and uncover a novel translation start for the published human isoform, MKL1_L. Using a human adipose-derived mesenchymal stem cell differentiation model, we show that TGF-β specifically upregulates MKL1_S during the initial phase of myofibroblast differentiation. We identified a functional N-terminal motif in MKL1_S that allows specific induction of a group of genes including the extracellular matrix (ECM) modifiers MMP16 and SPOCK3/testican-3. We propose that TGF-β-mediated induction of MKL1_S initiates progression to later stages of differentiation towards a stationary myofibroblast

Metamorphic evolution of exhumed middle to lower crustal rocks in the Mojave Extensional Belt, southern California, USA

The Waterman Metamorphic Complex of the central Mojave Desert was exposed as a consequence of early Miocene detachment‐dominated extension. However, it has evidence consistent with a more extensive geological history that involves collision of a crustal fragment(s), tectonic thickening by overthrusting and two periods of extension. The metamorphic complex contains granitoid intrusives and felsic mylonitic gneisses as well as polymetamorphic rocks that include marble, calc‐silicate, quartzite. mafic granulite, pyribolite, amphibolite, migmatite and biotite schist. The latter group of rocks was affected by an initial series of high‐grade metamorphic events (M1 and M2) and a localized lower grade overprint (M3). The initial metamorphism (M1) can be separated into two stages along its high‐grade P–T path: M1a, a granulite facies metamorphism at 800–850° C and 7.5–9 kbar and Mlb, an upper amphibolite facies overprint at 750–800° C and 10–12 kbar. M1a developed mineral assemblages and textures consistent with granulite facies conditions at a reduced activity of H2O and is associated with intense ductile deformation (D1) and minor local partial melting. M1b overprinted the granulite assemblages with a series of hydrous phases under conditions of increasing pressure and H2O activity and is accompanied by little or no deformation. M2 developed at lower pressures and temperatures (650–750° C, 4.5–5.5 kbar) and is distinguished by a second local overprint of hydrous phases that reflects an input of aqueous fluids probably associated with the intrusion of a series of granitic dykes and veins. Effects of M3 are confined to the Mitchel detachment zone, an anastomosing early Miocene detachment fault, and are characterized by local ductile/brittle deformation (D2) of the pre‐existing high‐grade rocks and granitoid intrusives and by the production of mylonites and mylonitic gneisses under greenschist facies conditions (300–350° C, 3–5 kbar). The initial overprint (M1a) represents metamorphism, devolatilization and minor partial melting of supracrustal rocks under granulite facies conditions as a consequence of tectonic and, possibly, magmatic thickening. The increasing pressure transition of M1a to M1b reflects a period of continued compressional tectonism, thrusting and influx of H2O, in part, locally related to crystallization of partial melts. The near isothermal decompression between M1b and M2 probably represents a pre‐112‐Ma extensional episode that may have been the result of a decompressional readjustment of a thickened crust. Following the initial extensional event, the metamorphic complex remained at depths of 10–17 km for at least 90 Ma until it was uplifted following Miocene extension. M3 develops locally in response to this second extensional period resulting from the early Miocene detachment faulting. Copyright © 1992, Wiley Blackwell. All rights reserve