beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.

2.50
Hdl Handle:
http://hdl.handle.net/11287/619731
Title:
beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.
Authors:
Frayling, T. M.; Evans, J. C.; Bulman, M. P.; Pearson, E. R.; Allen, Louisa; Owen, K.; Bingham, Coralie; Hannemann, Michael; Shepherd, Maggie ( 0000-0003-2660-0955 ) ; Ellard, Sian ( 0000-0002-7620-5526 ) ; Hattersley, Andrew T.
Abstract:
beta-Cell transcription factor genes are important in the pathophysiology of the beta-cell, with mutations in hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, insulin promoter factor (IPF)-1, HNF-1beta, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1alpha, 2% HNF-4alpha, 0% IPF-1, 1% HNF-1beta, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients including 29 new families and 8 novel HNF-1alpha gene mutations. Mutations in the transactivation domain are more likely to be protein truncating rather than result in amino acid substitutions, suggesting that a relatively severe disruption of this domain is necessary to result in diabetes. Mutations in the different transcription factors result in clinical heterogeneity. IPF-1 mutations are associated with a higher age at diagnosis (42.7 years) than HNF-1alpha (20.4 years), HNF-1beta (24.2 years), or HNF-4alpha (26.3 years) gene mutations. Subjects with HNF-1beta mutations, in contrast to the other transcription factors, frequently present with renal disease. A comparison of age at diagnosis between subjects with different types and locations of HNF-1alpha mutations did not reveal genotype-phenotype correlations. In conclusion, mutations in transcription factors expressed in the beta-cell are the major cause of MODY, and the phenotype clearly varies with the gene that is mutated. There is little evidence to indicate that different mutations within the same gene have different phenotypes.
Citation:
beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. 2001, 50 Suppl 1:S94-100 Diabetes
Publisher:
Highwire
Journal:
Diabetes
Issue Date:
Feb-2001
URI:
http://hdl.handle.net/11287/619731
PubMed ID:
11272211
Additional Links:
http://diabetes.diabetesjournals.org/content/50/suppl_1/S94.long
Note:
This article is freely available via Open Access. Click on the ‘Additional Link’ above to access the full-text from the publisher’s site.
Type:
Research Support, Non-U.S. Gov't
Language:
en
ISSN:
0012-1797
Appears in Collections:
pre-2014 RD&E publications; Exeter Kidney Unit (Renal); Diabetes/Endocrine Services; Obstetrics, Gynaecology & Maternity Services; Clinical Genetics (Peninsula Genetics); Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorFrayling, T. M.en
dc.contributor.authorEvans, J. C.en
dc.contributor.authorBulman, M. P.en
dc.contributor.authorPearson, E. R.en
dc.contributor.authorAllen, Louisaen
dc.contributor.authorOwen, K.en
dc.contributor.authorBingham, Coralieen
dc.contributor.authorHannemann, Michaelen
dc.contributor.authorShepherd, Maggieen
dc.contributor.authorEllard, Sianen
dc.contributor.authorHattersley, Andrew T.en
dc.date.accessioned2016-09-02T11:31:51Z-
dc.date.available2016-09-02T11:31:51Z-
dc.date.issued2001-02-
dc.identifier.citationbeta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. 2001, 50 Suppl 1:S94-100 Diabetesen
dc.identifier.issn0012-1797-
dc.identifier.pmid11272211-
dc.identifier.urihttp://hdl.handle.net/11287/619731-
dc.description.abstractbeta-Cell transcription factor genes are important in the pathophysiology of the beta-cell, with mutations in hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, insulin promoter factor (IPF)-1, HNF-1beta, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1alpha, 2% HNF-4alpha, 0% IPF-1, 1% HNF-1beta, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients including 29 new families and 8 novel HNF-1alpha gene mutations. Mutations in the transactivation domain are more likely to be protein truncating rather than result in amino acid substitutions, suggesting that a relatively severe disruption of this domain is necessary to result in diabetes. Mutations in the different transcription factors result in clinical heterogeneity. IPF-1 mutations are associated with a higher age at diagnosis (42.7 years) than HNF-1alpha (20.4 years), HNF-1beta (24.2 years), or HNF-4alpha (26.3 years) gene mutations. Subjects with HNF-1beta mutations, in contrast to the other transcription factors, frequently present with renal disease. A comparison of age at diagnosis between subjects with different types and locations of HNF-1alpha mutations did not reveal genotype-phenotype correlations. In conclusion, mutations in transcription factors expressed in the beta-cell are the major cause of MODY, and the phenotype clearly varies with the gene that is mutated. There is little evidence to indicate that different mutations within the same gene have different phenotypes.en
dc.language.isoenen
dc.publisherHighwireen
dc.relation.urlhttp://diabetes.diabetesjournals.org/content/50/suppl_1/S94.longen
dc.rightsArchived with thanks to Diabetesen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titlebeta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.en
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalDiabetesen
dc.description.noteThis article is freely available via Open Access. Click on the ‘Additional Link’ above to access the full-text from the publisher’s site.en
dc.type.versionPublisheden

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