10.5061/DRYAD.VDNCJSXVS
Yoshiji, Satoshi
0000-0001-8863-2413
Kitano Hospital
Horikawa, Yukio
0000-0001-7268-6871
Gifu University
Kubota, Sodai
Gifu University
Enya, Mayumi
Gifu University
Iwasaki, Yorihiro
Massachusetts General Hospital
Keidai, Yamato
Kitano Hospital
Aizawa-Abe, Megumi
Kitano Hospital
Iwasaki, Kanako
Kitano Hospital
Honjo, Sachiko
Kitano Hospital
Hosomichi, Kazuyoshi
Kanazawa University
Yabe, Daisuke
0000-0002-5334-7687
Gifu University
Hamasaki, Akihiro
Kitano Hospital
Identification of the first Japanese family with PDX1-MODY (MODY4): a
novel PDX1 frameshift mutation, clinical characteristics, and implications
Dryad
dataset
2021
FOS: Clinical medicine
2021-12-01T00:00:00Z
2021-12-01T00:00:00Z
en
https://doi.org/10.1210/jendso/bvab159
280416 bytes
8
CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Context The PDX1 encodes pancreatic and duodenal homeobox, a critical
transcription factor for pancreatic β-cell differentiation and maintenance
of mature β-cells. Heterozygous loss-of-function mutations cause PDX1-MODY
(MODY4). Case description The patient is an 18-year-old lean man who
developed diabetes at 16 years of age. Given his early-onset age and
leanness, we performed genetic testing. Targeted-next generation
sequencing and subsequent Sanger sequencing detected a novel heterozygous
frameshift mutation (NM_00209.4:c.218delT. NP_000200.1: p.Leu73Profs*50)
in the PDX1 transactivation domain that resulted in loss-of-function and
was validated by an in vitro functional study. The proband and his
56-year-old father, who had the same mutation, both showed markedly
reduced insulin and gastric inhibitory polypeptide (GIP) secretion
compared to the dizygotic twin sister, who was negative for the mutation
and had normal glucose tolerance. The proband responded to sitagliptin,
suggesting its utility as a treatment option. Notably, the proband and his
father showed intriguing phenotypic differences: the proband had been lean
for his entire life but developed early-onset diabetes requiring an
antihyperglycemic agent. In contrast, his father was overweight, developed
diabetes much later in life, and did not require medication, suggesting
the oligogenic nature of PDX1-MODY. A review of all reported cases of
PDX1-MODY also showed heterogeneous phenotypes regarding onset age,
obesity, and treatment, even in the presence of the same mutation.
Conclusions We identified the first Japanese family with PDX1-MODY. The
similarities and differences found among the cases highlight the wide
phenotypic spectrum of PDX1-MODY.
Oral glucose tolerance test For the 75g-oral glucose tolerance test,
Plasma GIP and GLP-1 (glucagon-like peptide-1) concentrations were
evaluated using a human active GIP ELISA kit (IBL Co Ltd, Fujioka, Japan)
and human active GLP-1 ELISA kit (Millipore, Billerica, USA),
respectively. Plasma glucagon levels were measured by a glucagon
enzyme-linked immunosorbent assay (ELISA) kit (Mercodia, Uppsala, Sweden).
Other laboratory measurements were performed by standard assays. Sanger
sequencing Sanger sequencing was performed following PCR amplification
with primers included in the present dataset.
Supplementary Figure 1. The 75-g oral glucose tolerance test (OGTT).
Plasma glucose (mg/dL), insulin (µL/mL), and insulin (µL/mL) to glucose
(mg/dL) ratio of the proband, his father, his dizygotic twin sister, and
his mother during the 75-g OGTT. Red line: proband (mutation-positive);
blue line: father (mutation-positive); black line: dizygotic sister
(mutation-negative); gray line: mother (mutation-negative). Supplementary
Figure 2. The 75-g oral glucose tolerance test (OGTT) with
glucose-dependent insulinotropic polypeptide (GIP) and other incretin
hormones. Plasma glucose (mg/dL), GIP (pmol/L), insulin (µL/mL), GLP-1
(pmol/L), and glucagon (pmol/L) of the mutation-positive individuals
(proband and his father), and the mutation-negative control (proband’s
dizygotic twin sister) during the 75-g OGTT. For incretin measurements,
the proband underwent another OGTT with a short duration (measured time:
0, 30, 60, 120 min); The proband’s glucose values differed from those in
Figure 1 and Supplementary figure 1. Incretin values were not available
for his mother. Red line: proband (mutation-positive); blue line: father
(mutation-positive); black line: dizygotic sister (mutation-negative). GIP
= Glucose-dependent insulinotropic polypeptide, GLP-1 = Glucagon-like
peptide-1. Supplementary Figure 3. Sanger sequencing of PDX1 in the
proband, his father, his dizygotic twin sister, and his mother. The
mutation (c.218delT) is shown with a red arrowhead, and the corresponding
wild-type allele is indicated by a black arrowhead. Mutant = Mutated
sequence, Wild = Wild-type sequence.