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.