De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs

De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs

Electrical conductivity structure of the lithosphere in western Fennoscandia from three-dimensional magnetotelluric data

Abstract The lithospheric conductivity in the westernmost Fennoscandia has been studied using magnetotelluric (MT) data. The western margin of Fennoscandia was significantly affected in Paleozoic by the Caledonian orogeny and later by the rifting of Laurentia and the opening of the Atlantic Ocean c. 80 Ma ago. Magnetotelluric studies have been carried out in two target areas in southern Norway and in western Fennoscandia. The first study resulted in 2-D geoelectric models of two profiles stretching from Oslo to the Norwegian coast. The interpretation suggests that the basement is in general very resistive with a few conductive upper crustal layers, representing the alum shales, and middle crustal conductors possibly imaging the remnants of the closed ocean basins. A more extensive MT study was performed within the project "Magnetotellurics in the Scandes". Measurements were carried in summers of 2011 to 2013, resulting in an array of 279 MT sites. The data allowed us to derive 2-D geoelectric models for the crust and upper mantle as well as 3-D models for the crust. The inversions revealed a resistive upper crust and a conductive lower crust, two upper crustal conductors in the Skellefteå and Kittilä districts, highly conducting alum shales in the Caledonides and a conductive upper crust beneath the Lofoten peninsula. The thickness of the lithosphere is around 200 km in the north and 300 km in the south-west. The Palaeoproterozoic lithosphere is the thickest, not the Archaean, on contrary to a generally accepted hypothesis. A better image of the lithosphere will help to evaluate the proposed mechanisms of the exhumation of the Scandinavian Mountains. The theoretical part of this study is the development of a new multi-resolution approach to 3-D electromagnetic (EM) modelling. Three-dimensional modelling of MT data requires enormous computational resources because of the huge number of data and model parameters. The development of the multi-resolution forward solver is based on the fact that a finer grid resolution is often required near the surface. On the other hand, the EM fields propagate in a diffusive manner and can be sufficiently well described on a grid that becomes coarser with depth. Tests showed that the total run time can be reduced by five times and the memory requirements by three times compared with the standard staggered grid forward solver.Tiivistelmä Olemme tutkineet litosfäärin sähkönjohtavuutta Fennoskandian länsiosassa magnetotelluurisen (MT) menetelmän avulla. Fennoskandian länsireuna muokkautui merkittävästi paleotsooisena aikana Kaledonidien vuorijonopoimutuksessa sekä myöhemmin mesotsooisena aikana Laurentia-mantereen repeytyessä ja Atlantin valtameren syntyessä noin 80 miljoonaa vuotta sitten. MT-tutkimukset tehtiin Etelä-Norjassa ja Fennoskandian luoteisosassa. Ensimmäisessä tutkimuksessa kallioperän sähkönjohtavuutta kuvattiin kaksiulotteisilla (2-D) johtavuusmalleilla, jotka ulottuvat Oslosta Norjan rannikolle. Mallien tulkinta viittaa siihen, että maan kuori on pääosin hyvin eristävä lukuun ottamatta muutamaa kuoren ylä- ja keskiosassa olevaa johdekerrosta. Yläkuoren johteet edustavat alunaliuskeita ja keskikuoren johteet todennäköisesti suljetuissa merialtaissa syntyneitä hiilipitoisia sedimenttikerrostumia. Laajempi MT-tutkimus tehtiin ”Magnetotellurics in the Scandes” -hankkeessa. Mittauksia tehtiin 279 mittauspisteessä kesinä 2011–2013. Saadun aineiston avulla voitiin laatia 2-D inversiomallit kuoresta ja ylävaipasta sekä 3-D inversiomalli kuoresta. Tulosten mukaan täällä kuoren yläosa on eristävä kun taas kuoren alaosa on sähköä hyvin johtava. Edellisen lisäksi malleissa näkyy yläkuoren johtavat muodostumat Skellefteån ja Kittilän alueilla, korkean johtavuuden alunaliuskeet Kaledonidien alueella sekä johde Lofoottien alla. Litosfäärin paksuus on noin 200 km mittausverkon pohjoisosassa ja noin 300 km lounaassa. Tämän mukaan litosfääri on paksuin varhaisproterotsooisen litosfäärin alueella, ei arkeeisen litosfäärin alueella vastoin yleistä hypoteesia. Tutkimuksen teoreettisessa osassa kehitettiin sähkömagneettiseen mallinnukseen uusi monitasoiseen diskretisointiin perustuva menetelmä. MT-aineiston 3-D käänteisongelman ratkaisu ja siihen liittyvä suora mallintaminen vaativat suuren laskennallisen kapasiteetin, koska havaintojen ja mallin kuvaamiseen tarvittavien parametrien määrä on erittäin suuri. Moniresoluutio-algoritmi perustuu siihen, että mallin hienojakoisempaa diskretisointia tarvitaan yleensä lähellä maan pintaa kun taas syvemmälle edettäessä, sähkömagneettisen aallon diffuusin etenemisen vuoksi, malli voi olla karkeampi. Tietokonesimulaatioiden mukaan suoritusaika on viidennes ja muistitarve kolmannes verrattuna tavanomaiseen suoran laskennan ”staggered grid” -diskretisointiin

Magnetotelluric array data analysis from north-west Fennoscandia

New magnetotelluric (MT) data in north-west Fennoscandia were acquired within the framework of the project Magnetotellurics in the Scandes (MaSca). The project focuses on the investigation of the crustal and upper mantle lithospheric structure in the transition zone from stable Precambrian cratonic interior to passive continental margin beneath the Caledonian orogen and the Scandinavian Mountains in western Fennoscandia. An array of 59 synchronous long period and 220 broad-band MT sites was occupied in the summers of 2011 to 2013. We estimated MT transfer functions in the period range from 0.003 to 10(5) s. The Q-function multi-site multi-frequency analysis and the phase tensor were used to estimate strike and dimensionality of MT data. Dimensionality and strike analyses indicate generally 2-D behaviour of the data with 3-D effects at some sites and period bands. In this paper we present 2-D inversion of the data, 3-D inversion models are shown in the parallel paper. We choose to invert the determinant of the impedance tensor to mitigate 3-D effects in the data on our 2-D models. Seven crustal-scale and four lithospheric-scale 2-D models are presented. The resistive regions are images of the Archaean and Proterozoic basement in the east and thin Caledonian nappes in the west. The middle and lower crust of the Svecofennian province is conductive. The southern end of the Kittila Greenstone Belt is seen in the models as a strong upper to middle crustal conductor. In the Caledonides, the highly conductive alum shales are observed along the Caledonian Thrust Front. The thickest lithosphere is in the Palaeoproterozioc Svecofennian Domain, not in the Archaean. The thickness of the lithosphere is around 200 km in the north and 300 km in the south-west. (c) 2015 Elsevier B.V. All rights reserved