maturity-onset diabetes of the young (mody) - GGH Journal

The identity of the MODY3 locus also was determined
by a positional cloning approach. In 1996, a cytosine
insertion was identified in codon 291 of HNF-1a
(P291fsdeIC). This segregated with OM in a MOOY3
pedigree. This particular mutant of the HNF-1a gene
is a frameshifted truncated protein that appears to
function in a dominant negative manner.18 Mutations
(57 to date) in MODY3 are highly prevalent, accounting
for 64% of MOOY in the United Kingdom, 30% of
early-onset type 2 OM in Germany, and 15% to 20% of
MOOY in Japan. The P291fsdeiC mutation has
appeared in at least 9 distinct haplotypes in Germany,
Britain, the United States, Sweden, and Japan, implying
the existence of a mutational hot spot. HNF-1a
appears to regulate transcription of the insulin gene,
the GLUT2 gene, and other genes encoding components
of the r3-cell glycolytic pathway.
The most recently described MOOY gene (MODY5)
encodes HNF-1[3, another member of the transcriptional
regulatory network that includes HNF-1a and HNF-4a
(Table 3). The HNF-1f3 gene was screened because it
was known that HNF-1[3 can function as a heterodimerization
partner with HNF-1a. A nonsense mutation in
HNF-1f3, R177X, was identified in a small Japanese
pedigree with early onset of OM at age 10 and 15, but
one member developed OM later, at age 40.12 All had
evidence of diabetic neuropathy. Subsequent screens
have identified 2 additional mutations in families with
early-onset OM and MOOY associated with renal failure
and renal cysts, and another mutation in late-onset type
2 OM not associated with kidney disease.
The identity of the MOOY 4 locus reflects the close
relationship between pancreatic development and
glucose homeostasis. Experimental gene inactivation
in mice is uncovering a growing number of transcription
factor genes whose normal expression is required
for full development of the exocrine and endocrine
pancreas (Table 4). These genes are being evaluated
as candidate diabetes genes. The first positive example
of this approach came from mice with homozygous
disruption of the IPF-1 gene and resultant total
pancreatic agenesis. IPF-1, a homeodomain transcription
factor, is implicated in the transcriptional
regulation of key ~-cell genes. In humans, the first
MODY 4 family was discovered when a rare subject
with pancreatic agenesis was found to be homozygous
for an inactivating cytosine deletion mutation in
the protein coding sequence of IPF-1 (Pro63fsdeIC).19
Subsequently, the heterozygous mutant allele within
both branches of the extended family of the proband
was linked to MODY.8 Three members of this pedigree
satisfy the strictest criteria for the diagnosis of
MODY, and 2 additional heterozygous subjects developed
diabetes or glucose intolerance by 30 years of
age, thus establishing IPF-1 as the MODY 4 gene. To
date, at least 7 additional heterozygous IPF-1 mutations
have been discovered in approximately 5% to
6% of familial late-onset type 2 OM patients in France
and the United Kingdom and in a small number of
additional MOOY pedigrees.
THE FUTURE
While the recent advances in MODY genetics have
been most exciting, there remain additional MODY
genes to be uncovered. In 2 MODY populations in
France and England, in which screening for possible
mutations in all 5 MODY genes has been undertaken,
the genetic defect in 16% to 20% of MODY pedigrees
remains a mystery. An ever-increasing number of
genes whose normal function is required for full development
of the pancreas are being identified through
analysis of the phenotypes of knockout mice (Table 4).20
Some of these genes probably will turn out to playa
role in human type 2 DM. In support of this
concept, several mutations in the human BETA2 gene
were recently reported in familial late-onset type 2
DM.21 Other members of the transcriptional regulatory
network of hepatocyte nuclear factors also are logical
candidate diabetes genes to consider.
Most MODY subjects exhibit decreased insulin secretion
and lean body mass. However, there are other
MODY pedigrees (in which mutations in MODY1,
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