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

2.50
Hdl Handle:
http://hdl.handle.net/11287/593830
Title:
Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
Authors:
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 ( 0000-0002-7620-5526 ) ; International, N. D. M. Consortium
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:
Oxford Journals
Journal:
Human molecular genetics
Issue Date:
15-Dec-2014
URI:
http://hdl.handle.net/11287/593830
DOI:
10.1093/hmg/ddu360
PubMed ID:
25015100
Additional Links:
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.
Type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1460-2083
Appears in Collections:
2014 RD&E publications; Molecular Genetics; Molecular Genetics; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorRaimondo, A.en
dc.contributor.authorChakera, Ali J.en
dc.contributor.authorThomsen, S. K.en
dc.contributor.authorColclough, Kevinen
dc.contributor.authorBarrett, A.en
dc.contributor.authorDe Franco, E.en
dc.contributor.authorChatelas, A.en
dc.contributor.authorDemirbilek, H.en
dc.contributor.authorAkcay, T.en
dc.contributor.authorAlawneh, H.en
dc.contributor.authorInternational, N. D. M. Consortiumen
dc.contributor.authorFlanagan, S. E.en
dc.contributor.authorVan De Bunt, M.en
dc.contributor.authorHattersley, Andrew T.en
dc.contributor.authorGloyn, A. L.en
dc.contributor.authorEllard, Sianen
dc.contributor.authorInternational, N. D. M. Consortiumen
dc.date.accessioned2016-01-19T12:35:29Zen
dc.date.available2016-01-19T12:35:29Zen
dc.date.issued2014-12-15en
dc.identifier.citationHum Mol Genet. 2014 Dec 15;23(24):6432-40.en
dc.identifier.issn1460-2083en
dc.identifier.pmid25015100en
dc.identifier.doi10.1093/hmg/ddu360en
dc.identifier.urihttp://hdl.handle.net/11287/593830en
dc.description.abstractMutations 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.en
dc.language.isoengen
dc.publisherOxford Journalsen
dc.relation.urlhttp://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=25015100en
dc.titlePhenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stabilityen
dc.typeJournal Articleen
dc.typeResearch Support, N.I.H., Extramuralen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalHuman molecular geneticsen
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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