Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis

OBJECTIVE: To demonstrate the importance of using a combined genetic and functional approach to correctly interpret a genetic test for monogenic diabetes. RESEARCH DESIGN AND METHODS: We identified three probands with a phenotype consistent with maturity-onset diabetes of the young (MODY) subtype GC...

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Autores principales: Beer, Nicola L., Osbak, Kara K., van de Bunt, Martijn, Tribble, Nicholas D., Steele, Anna M., Wensley, Kirsty J., Edghill, Emma L., Colcough, Kevin, Barrett, Amy, Valentínová, Lucia, Rundle, Jana K., Raimondo, Anne, Grimsby, Joseph, Ellard, Sian, Gloyn, Anna L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379612/
https://www.ncbi.nlm.nih.gov/pubmed/22611063
http://dx.doi.org/10.2337/dc11-2420
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author Beer, Nicola L.
Osbak, Kara K.
van de Bunt, Martijn
Tribble, Nicholas D.
Steele, Anna M.
Wensley, Kirsty J.
Edghill, Emma L.
Colcough, Kevin
Barrett, Amy
Valentínová, Lucia
Rundle, Jana K.
Raimondo, Anne
Grimsby, Joseph
Ellard, Sian
Gloyn, Anna L.
author_facet Beer, Nicola L.
Osbak, Kara K.
van de Bunt, Martijn
Tribble, Nicholas D.
Steele, Anna M.
Wensley, Kirsty J.
Edghill, Emma L.
Colcough, Kevin
Barrett, Amy
Valentínová, Lucia
Rundle, Jana K.
Raimondo, Anne
Grimsby, Joseph
Ellard, Sian
Gloyn, Anna L.
author_sort Beer, Nicola L.
collection PubMed
description OBJECTIVE: To demonstrate the importance of using a combined genetic and functional approach to correctly interpret a genetic test for monogenic diabetes. RESEARCH DESIGN AND METHODS: We identified three probands with a phenotype consistent with maturity-onset diabetes of the young (MODY) subtype GCK-MODY, in whom two potential pathogenic mutations were identified: [R43H/G68D], [E248 K/I225M], or [G261R/D217N]. Allele-specific PCR and cosegregation were used to determine phase. Single and double mutations were kinetically characterized. RESULTS: The mutations occurred in cis (double mutants) in two probands and in trans in one proband. Functional studies of all double mutants revealed inactivating kinetics. The previously reported GCK-MODY mutations R43H and G68D were inherited from an affected father and unaffected mother, respectively. Both our functional and genetic studies support R43H as the cause of GCK-MODY and G68D as a neutral rare variant. CONCLUSIONS: These data highlight the need for family/functional studies, even for previously reported pathogenic mutations.
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spelling pubmed-33796122013-07-01 Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis Beer, Nicola L. Osbak, Kara K. van de Bunt, Martijn Tribble, Nicholas D. Steele, Anna M. Wensley, Kirsty J. Edghill, Emma L. Colcough, Kevin Barrett, Amy Valentínová, Lucia Rundle, Jana K. Raimondo, Anne Grimsby, Joseph Ellard, Sian Gloyn, Anna L. Diabetes Care Original Research OBJECTIVE: To demonstrate the importance of using a combined genetic and functional approach to correctly interpret a genetic test for monogenic diabetes. RESEARCH DESIGN AND METHODS: We identified three probands with a phenotype consistent with maturity-onset diabetes of the young (MODY) subtype GCK-MODY, in whom two potential pathogenic mutations were identified: [R43H/G68D], [E248 K/I225M], or [G261R/D217N]. Allele-specific PCR and cosegregation were used to determine phase. Single and double mutations were kinetically characterized. RESULTS: The mutations occurred in cis (double mutants) in two probands and in trans in one proband. Functional studies of all double mutants revealed inactivating kinetics. The previously reported GCK-MODY mutations R43H and G68D were inherited from an affected father and unaffected mother, respectively. Both our functional and genetic studies support R43H as the cause of GCK-MODY and G68D as a neutral rare variant. CONCLUSIONS: These data highlight the need for family/functional studies, even for previously reported pathogenic mutations. American Diabetes Association 2012-07 2012-06-12 /pmc/articles/PMC3379612/ /pubmed/22611063 http://dx.doi.org/10.2337/dc11-2420 Text en © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Beer, Nicola L.
Osbak, Kara K.
van de Bunt, Martijn
Tribble, Nicholas D.
Steele, Anna M.
Wensley, Kirsty J.
Edghill, Emma L.
Colcough, Kevin
Barrett, Amy
Valentínová, Lucia
Rundle, Jana K.
Raimondo, Anne
Grimsby, Joseph
Ellard, Sian
Gloyn, Anna L.
Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis
title Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis
title_full Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis
title_fullStr Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis
title_full_unstemmed Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis
title_short Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis
title_sort insights into the pathogenicity of rare missense gck variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379612/
https://www.ncbi.nlm.nih.gov/pubmed/22611063
http://dx.doi.org/10.2337/dc11-2420
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