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

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...

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Autores principales: Raimondo, Anne, Chakera, Ali J., Thomsen, Soren K., Colclough, Kevin, Barrett, Amy, De Franco, Elisa, Chatelas, Alisson, Demirbilek, Huseyin, Akcay, Teoman, Alawneh, Hussein, Flanagan, Sarah E., Van De Bunt, Martijn, Hattersley, Andrew T., Gloyn, Anna L., Ellard, Sian, Abduljabbar, Mohammad A., Al-Zyoud, Mahmoud, Aman, Syed, Bath, Louise, De, Parijat, Deshpande, Neeta, Durmaz, Erdem, Eickmeier, Frank, Elbarbary, Nancy Samir, Fillion, Marc, Jagadeesh, Sujatha M., Kershaw, Melanie, Khan, Waqas I., Mlynarski, Wojciech, Noyes, Kathryn, Peters, Catherine J., Shaw, Nick, Tiron, Irina, Turkkahraman, Doga, Turner, Lesley, Eltonbary, Khadiga Y., Yuksel, Bilgin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240195/
https://www.ncbi.nlm.nih.gov/pubmed/25015100
http://dx.doi.org/10.1093/hmg/ddu360
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author Raimondo, Anne
Chakera, Ali J.
Thomsen, Soren K.
Colclough, Kevin
Barrett, Amy
De Franco, Elisa
Chatelas, Alisson
Demirbilek, Huseyin
Akcay, Teoman
Alawneh, Hussein
Flanagan, Sarah E.
Van De Bunt, Martijn
Hattersley, Andrew T.
Gloyn, Anna L.
Ellard, Sian
Abduljabbar, Mohammad A.
Al-Zyoud, Mahmoud
Aman, Syed
Bath, Louise
De, Parijat
Deshpande, Neeta
Durmaz, Erdem
Eickmeier, Frank
Elbarbary, Nancy Samir
Fillion, Marc
Jagadeesh, Sujatha M.
Kershaw, Melanie
Khan, Waqas I.
Mlynarski, Wojciech
Noyes, Kathryn
Peters, Catherine J.
Shaw, Nick
Tiron, Irina
Turkkahraman, Doga
Turner, Lesley
Eltonbary, Khadiga Y.
Yuksel, Bilgin
author_facet Raimondo, Anne
Chakera, Ali J.
Thomsen, Soren K.
Colclough, Kevin
Barrett, Amy
De Franco, Elisa
Chatelas, Alisson
Demirbilek, Huseyin
Akcay, Teoman
Alawneh, Hussein
Flanagan, Sarah E.
Van De Bunt, Martijn
Hattersley, Andrew T.
Gloyn, Anna L.
Ellard, Sian
Abduljabbar, Mohammad A.
Al-Zyoud, Mahmoud
Aman, Syed
Bath, Louise
De, Parijat
Deshpande, Neeta
Durmaz, Erdem
Eickmeier, Frank
Elbarbary, Nancy Samir
Fillion, Marc
Jagadeesh, Sujatha M.
Kershaw, Melanie
Khan, Waqas I.
Mlynarski, Wojciech
Noyes, Kathryn
Peters, Catherine J.
Shaw, Nick
Tiron, Irina
Turkkahraman, Doga
Turner, Lesley
Eltonbary, Khadiga Y.
Yuksel, Bilgin
author_sort Raimondo, Anne
collection PubMed
description 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.
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spelling pubmed-42401952014-11-21 Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability Raimondo, Anne Chakera, Ali J. Thomsen, Soren K. Colclough, Kevin Barrett, Amy De Franco, Elisa Chatelas, Alisson Demirbilek, Huseyin Akcay, Teoman Alawneh, Hussein Flanagan, Sarah E. Van De Bunt, Martijn Hattersley, Andrew T. Gloyn, Anna L. Ellard, Sian Abduljabbar, Mohammad A. Al-Zyoud, Mahmoud Aman, Syed Bath, Louise De, Parijat Deshpande, Neeta Durmaz, Erdem Eickmeier, Frank Elbarbary, Nancy Samir Fillion, Marc Jagadeesh, Sujatha M. Kershaw, Melanie Khan, Waqas I. Mlynarski, Wojciech Noyes, Kathryn Peters, Catherine J. Shaw, Nick Tiron, Irina Turkkahraman, Doga Turner, Lesley Eltonbary, Khadiga Y. Yuksel, Bilgin Hum Mol Genet Articles 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. Oxford University Press 2014-12-15 2014-07-11 /pmc/articles/PMC4240195/ /pubmed/25015100 http://dx.doi.org/10.1093/hmg/ddu360 Text en © The Author 2014. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Raimondo, Anne
Chakera, Ali J.
Thomsen, Soren K.
Colclough, Kevin
Barrett, Amy
De Franco, Elisa
Chatelas, Alisson
Demirbilek, Huseyin
Akcay, Teoman
Alawneh, Hussein
Flanagan, Sarah E.
Van De Bunt, Martijn
Hattersley, Andrew T.
Gloyn, Anna L.
Ellard, Sian
Abduljabbar, Mohammad A.
Al-Zyoud, Mahmoud
Aman, Syed
Bath, Louise
De, Parijat
Deshpande, Neeta
Durmaz, Erdem
Eickmeier, Frank
Elbarbary, Nancy Samir
Fillion, Marc
Jagadeesh, Sujatha M.
Kershaw, Melanie
Khan, Waqas I.
Mlynarski, Wojciech
Noyes, Kathryn
Peters, Catherine J.
Shaw, Nick
Tiron, Irina
Turkkahraman, Doga
Turner, Lesley
Eltonbary, Khadiga Y.
Yuksel, Bilgin
Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
title Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
title_full Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
title_fullStr Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
title_full_unstemmed Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
title_short Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
title_sort phenotypic severity of homozygous gck mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240195/
https://www.ncbi.nlm.nih.gov/pubmed/25015100
http://dx.doi.org/10.1093/hmg/ddu360
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