Identification of the first Japanese family with PDX1-MODY (MODY4): a novel PDX1 frameshift mutation, clinical characteristics, and implications

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.