• Login
    View Item 
    •   RD&E Research Repository Home
    • All RD&E publications by year
    • 2014 RD&E publications
    • View Item
    •   RD&E Research Repository Home
    • All RD&E publications by year
    • 2014 RD&E publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability

    Thumbnail
    URI
    http://hdl.handle.net/11287/593830
    Author
    Raimondo, A.
    Chakera, Ali J.
    Thomsen, S. K.
    Colclough, Kevin
    Barrett, A.
    De Franco, E.
    Chatelas, A.
    Demirbilek, H.
    Akcay, T.
    Alawneh, H.
    International, N. D. M. Consortium
    Flanagan, S. E.
    Van De Bunt, M.
    Hattersley, Andrew T.
    Gloyn, A. L.
    Ellard, Sian
    International, N. D. M. Consortium
    Date
    2014-12-15
    Journal
    Human molecular genetics
    Type
    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Publisher
    Oxford Journals
    DOI
    10.1093/hmg/ddu360
    Metadata
    Show full item record
    Abstract
    Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI </= 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.
    Citation
    Hum Mol Genet. 2014 Dec 15;23(24):6432-40.
    Publisher URL
    http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=25015100
    Note
    This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
    Collections
    • 2014 RD&E publications
    • Honorary contracts publications
    • Molecular Genetics

    Browse

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

    My Account

    LoginRegister

    DSpace software copyright © 2002-2023  DuraSpace
    Contact Us | Send Feedback
    DSpace Express is a service operated by 
    Atmire NV