• Login
    View Item 
    •   RD&E Research Repository Home
    • All RD&E publications by year
    • 2015 RD&E publications
    • View Item
    •   RD&E Research Repository Home
    • All RD&E publications by year
    • 2015 RD&E publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73

    Thumbnail
    URI
    http://hdl.handle.net/11287/594019
    Author
    Jinks, R. N.
    Puffenberger, E. G.
    Baple, E.
    Harding, B.
    Crino, P.
    Fogo, A. B.
    Wenger, O.
    Xin, B.
    Koehler, A. E.
    McGlincy, M. H.
    Provencher, M. M.
    Smith, J. D.
    Tran, L.
    Al Turki, S.
    Chioza, Barry A.
    Cross, H.
    Harlalka, G. V.
    Hurles, M. E.
    Maroofian, R.
    Heaps, A. D.
    Morton, M. C.
    Stempak, L.
    Hildebrandt, F.
    Sadowski, C. E.
    Zaritsky, J.
    Campellone, K.
    Morton, D. H.
    Wang, H.
    Crosby, Andrew
    Strauss, K. A.
    Date
    2015-06-11
    Journal
    Brain : a journal of neurology
    Type
    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Publisher
    Oxford Journals
    DOI
    10.1093/brain/awv153
    Metadata
    Show full item record
    Abstract
    We describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with alpha-, beta-, and gamma-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs*26 and p.Arg256Profs*18 proteins are truncated, unstable, and show increased interaction with alpha- and beta-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.
    Citation
    Brain. 2015 Aug;138(Pt 8):2173-90.
    Publisher URL
    http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=26070982
    Note
    This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
    Collections
    • 2015 RD&E publications
    • Honorary contracts publications

    Browse

    All of RD&E Research RepositoryCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    DSpace software copyright © 2002-2021  DuraSpace
    Contact Us | Send Feedback
    DSpace Express is a service operated by 
    Atmire NV