Rare variants identified in the HNF- 4 alpha beta-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes.
OBJECTIVE
The recently identified alternative promoter (P2) of HNF-4 alpha is the major HNF-4 alpha transcription start site in pancreatic beta cells. The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family. The role of the P2 promoter and the associated alternative exon 1 in both MODY and polygenic Type II (non-insulin-dependent) diabetes mellitus is not known. Linkage to this region in studies of Type II diabetes makes the P2 region a strong candidate for a role in Type II diabetes susceptibility.


METHODS
To assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4 alpha.


RESULTS
Two variants were found that were not present in the control subjects. The -79 C/T substitution was present in a MODY family but did not perfectly cosegregate with diabetes. A -276 G/T substitution was identified in two UK young-onset diabetes probands but did not co-segregate with diabetes. Reporter gene studies did not indicate changes in transcriptional activity caused by either the -79 C/T or -276 G/T single nucleotide substitutions.


CONCLUSIONS
We found no evidence to suggest that variation in the P2 proximal promoter region and associated alternative exon 1 of HNF-4 alpha contribute to young onset Type II diabetes susceptibility in Northern Europeans.
Mitchell
S M S
SM
Department of Diabetes and Vascular Medicine, University of Exeter, Exeter, UK.
Vaxillaire
M
M
Thomas
H
H
Parrizas
M
M
Benmezroua
Y
Y
Costa
A
A
Hansen
T
T
Owen
K R
KR
Tuomi
T
T
Pirie
F
F
Ryffel
G U
GU
Ferrer
J
J
Froguel
P
P
Hattersley
A T
AT
Frayling
T M
TM
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002648:Child; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; D014157:Transcription Factors