PDX1 – Maturity-Onset Diabetes of the Young (MODY4)

Maturity-onset diabetes of the young (MODY) subtype 4 is an autosomal dominant monogenic diabetes characterized by early onset and primary β-cell dysfunction. The PDX1 gene encodes a homeodomain transcription factor essential for pancreatic development and insulin production. Heterozygous loss-of-function variants in PDX1 reduce β-cell transcriptional activity and increase susceptibility to MODY and gestational diabetes (PMID:16092045).

Genetic evidence derives from two pedigrees: an Italian family (Italy-6) in which a c.97C>A (p.Pro33Thr) variant was found in 9 of 22 genotyped members, 5 of whom exhibited diabetes or impaired fasting glucose (PMID:16092045), and an Indo-Trinidadian family carrying c.670G>A (p.Glu224Lys), which cosegregated with early-onset diabetes in multiple affected relatives (PMID:14764823). No recurrent deep-intronic or structural variants have been reported in these families.

Segregation analysis identified 5 affected heterozygous carriers in the Italy-6 pedigree and multiple diabetic relatives in the E224K family, supporting autosomal dominant transmission. Overall, fewer than ten families have been described with PDX1 missense alleles and diabetes, limiting cohort size and precluding extensive segregation mapping.

Functional assays demonstrate that P33T and Glu224Lys proteins have significantly reduced DNA-binding affinity and impaired transcriptional activation of insulin and β-cell target promoters, consistent with a haploinsufficiency mechanism (PMID:16092045; PMID:14764823). These in vitro data concord with the human phenotypes of early-onset diabetes and gestational glucose intolerance.

No studies have refuted the role of PDX1 in MODY4, although PDX1 variants are rare and contribute to a small fraction of MODY cases compared to HNF1A or GCK. Additional evidence from animal models and broader population screens remains limited but would strengthen the association.

PDX1 variant testing can confirm MODY4 diagnoses in families with early-onset diabetes and guide precision management, including surveillance for gestational diabetes. Key Take-home: Heterozygous PDX1 missense variants cause autosomal dominant MODY4 via haploinsufficiency and confer risk for gestational and early-onset diabetes.

References

• Metabolism: clinical and experimental • 2005 • IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. PMID:16092045
• The Journal of clinical endocrinology and metabolism • 2004 • Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family. PMID:14764823

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