First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications

Abstract

Context The PDX1 gene 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 Our 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 with the dizygotic twin sister, who was negative for the mutation and had normal glucose tolerance. The proband responded well 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.

Maturity‐onset diabetes of the young (MODY) due to PDX1 mutation in a sib‐pair diabetes family from Qatar

“…However, the proband's father with the same mutation was obese with later-onset diabetes and did not need any medication. 8 There is heterogeneity in the clinical phenotype observed in PDX1 MODY cases in the literature. In our patients, there is an amino acid substitution from proline to threonine (p. Pro33Thr).…”

MNX1 mutations causing neonatal diabetes: Review of the literature and report of a case with extra‐pancreatic congenital defects presenting in severe diabetic ketoacidosis

“…GATA6 haploinsufficiency 20 , 21 , 22 and GATA4 mutations 23 were reported to result in a wide phenotypic spectrum of diabetes (from PNDM to adult‐onset diabetes), exocrine pancreatic affection, and variable heart defects in individuals carrying the same mutation. There are also few reports of variable presentation of diabetes in patients carrying the exact same PDX‐1 genotypic mutation (from early‐onset MODY 4 diabetes, gestational diabetes progressing to type 2 diabetes, or later‐onset MODY‐diabetes) 24 , 25 . Interestingly, the two male cases with MNX1 mutations causing diabetes had a syndromic presentation whereas the female case had isolated PNDM.…”

From glucose sensing to exocytosis: takes from maturity onset diabetes of the young

“…PDX1 ( Table 1 ) is a homeodomain-containing transcription factor, possesses a N-terminal transactivation domain, a C-terminal domain and a DNA-binding homeodomain (HD), which are hot-spot regions for mutations ( Figure 2 ) ( 106 ). Depending upon the mode of inheritance, location and penetrance of the mutation, PDX1 gene alterations result in partial and total pancreatic agenesis ( 107 ), ND without exocrine insufficiency ( 108 ), gestational diabetes ( 93 ), and MODY with variable age at onset and severity ( 106 ).…”