Novel mutations and a mutational hotspot in the MODY3 gene.
Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) located on chromosome 12q. We have identified four novel HNF-1alpha missense mutations in MODY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in MODY3. We observed no HNF-1alpha mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes.
Glucksmann
M A
MA
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Lehto
M
M
Tayber
O
O
Scotti
S
S
Berkemeier
L
L
Pulido
J C
JC
Wu
Y
Y
Nir
W J
WJ
Fang
L
L
Markel
P
P
Munnelly
K D
KD
Goranson
J
J
Orho
M
M
Young
B M
BM
Whitacre
J L
JL
McMenimen
C
C
Wantman
M
M
Tuomi
T
T
Warram
J
J
Forsblom
C M
CM
Carlsson
M
M
Rosenzweig
J
J
Kennedy
G
G
Duyk
G M
GM
Thomas
J D
JD
D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005190:Family; D008040:Genetic Linkage; D006239:Haplotypes; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta