PMID- 10545951
OWN - NLM
STAT- MEDLINE
DCOM- 19991207
LR  - 20111117
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 23
IP  - 3
DP  - 1999 Nov
TI  - Mutations in NEUROD1 are associated with the development of type 2 diabetes
      mellitus.
PG  - 323-8
AB  - 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.
FAU - Malecki, M T
AU  - Malecki MT
AD  - Research Division, Joslin Diabetes Center, Harvard Medical School, Boston,
      Massachusetts, USA.
FAU - Jhala, U S
AU  - Jhala US
FAU - Antonellis, A
AU  - Antonellis A
FAU - Fields, L
AU  - Fields L
FAU - Doria, A
AU  - Doria A
FAU - Orban, T
AU  - Orban T
FAU - Saad, M
AU  - Saad M
FAU - Warram, J H
AU  - Warram JH
FAU - Montminy, M
AU  - Montminy M
FAU - Krolewski, A S
AU  - Krolewski AS
LA  - eng
SI  - GENBANK/AF045152
SI  - GENBANK/U50822
GR  - DK-36836/DK/NIDDK NIH HHS/United States
GR  - DK-47475/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Insulin)
RN  - 0 (NEUROD1 protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Trans-Activators)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - Basic Helix-Loop-Helix Transcription Factors
MH  - DNA/genetics/metabolism
MH  - DNA Mutational Analysis
MH  - DNA-Binding Proteins/chemistry/*genetics/metabolism
MH  - Diabetes Mellitus, Type 2/*genetics/metabolism/pathology
MH  - Female
MH  - Gene Expression Regulation
MH  - Heterozygote
MH  - Humans
MH  - Insulin/genetics
MH  - Male
MH  - Middle Aged
MH  - Molecular Sequence Data
MH  - Mutation/*genetics
MH  - Nuclear Proteins/metabolism
MH  - Pedigree
MH  - Polymorphism, Genetic/genetics
MH  - Response Elements/genetics
MH  - Sequence Deletion/genetics
MH  - Trans-Activators/chemistry/*genetics/metabolism
MH  - Tumor Cells, Cultured
EDAT- 1999/11/05 08:00
MHDA- 2001/03/23 10:01
CRDT- 1999/11/05 08:00
PHST- 1999/11/05 08:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/11/05 08:00 [entrez]
AID - 10.1038/15500 [doi]
PST - ppublish
SO  - Nat Genet. 1999 Nov;23(3):323-8. doi: 10.1038/15500.