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PMID:10545951

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Citation

Malecki, MT, Jhala, US, Antonellis, A, Fields, L, Doria, A, Orban, T, Saad, M, Warram, JH, Montminy, M and Krolewski, AS (1999) Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat. Genet. 23:323-8

Abstract

The helix-loop-helix (HLH) protein NEUROD1 (also known as BETA2) functions as a regulatory switch for endocrine pancreatic development. In mice homozygous for a targeted disruption of Neurod, pancreatic islet morphogenesis is abnormal and overt diabetes develops due in part to inadequate expression of the insulin gene (Ins2). NEUROD1, following its heterodimerization with the ubiquitous HLH protein E47, regulates insulin gene (INS) expression by binding to a critical E-box motif on the INS promoter. Here we describe two mutations in NEUROD1, which are associated with the development of type 2 diabetes in the heterozygous state. The first, a missense mutation at Arg 111 in the DNA-binding domain, abolishes E-box binding activity of NEUROD1. The second mutation gives rise to a truncated polypeptide lacking the carboxy-terminal trans-activation domain, a region that associates with the co-activators CBP and p300 (refs 3,4). The clinical profile of patients with the truncated NEUROD1 polypeptide is more severe than that of patients with the Arg 111 mutation. Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans.

Links

PubMed Online version:10.1038/15500

Keywords

Adolescent; Adult; Amino Acid Sequence; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; DNA/genetics; DNA/metabolism; DNA Mutational Analysis; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Diabetes Mellitus, Type 2/genetics; Diabetes Mellitus, Type 2/metabolism; Diabetes Mellitus, Type 2/pathology; Female; Gene Expression Regulation; Heterozygote; Humans; Insulin/genetics; Male; Middle Aged; Molecular Sequence Data; Mutation/genetics; Nuclear Proteins/metabolism; Pedigree; Polymorphism, Genetic/genetics; Response Elements/genetics; Sequence Deletion/genetics; Trans-Activators/chemistry; Trans-Activators/genetics; Trans-Activators/metabolism; Tumor Cells, Cultured

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TFE2

part_of

GO:0090575: RNA polymerase II transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NDF1

part_of

GO:0090575: RNA polymerase II transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NDF1

located_in

GO:0005634: nucleus

ECO:0000305: curator inference used in manual assertion

GO:0043565

C

Seeded From UniProt

complete

HUMAN:NDF1

involved_in

GO:0009749: response to glucose

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NDF1

involved_in

GO:0050796: regulation of insulin secretion

ECO:0000305: curator inference used in manual assertion

GO:0045944

P

Seeded From UniProt

complete

HUMAN:NDF1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NDF1

contributes_to

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0046982: protein heterodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15923

F

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15923

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0043425: bHLH transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13562

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0046982: protein heterodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13562

F

Seeded From UniProt

complete

HUMAN:TFE2

part_of

GO:0090575: RNA polymerase II transcription factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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