PDX1 – Permanent Neonatal Diabetes Mellitus

PDX1 has been implicated in permanent neonatal diabetes mellitus (PNDM) through autosomal-recessive hypomorphic mutations. A single consanguineous kindred with two first cousins homozygous for a novel c.533A>G (p.Glu178Gly) variant presented with permanent neonatal diabetes and subclinical exocrine insufficiency, while all heterozygous parents were non-diabetic (PMID:20009086). This variant segregates with disease in the homozygous state, defining an autosomal-recessive inheritance pattern.

Functional studies demonstrate that the p.Glu178Gly substitution in the PDX1 homeodomain reduces transactivation capacity despite normal protein stability, localization, and DNA binding, supporting a hypomorphic loss-of-function mechanism (PMID:20009086). These data establish limited but concordant genetic and functional evidence linking PDX1 to PNDM and support screening PDX1 in neonatal diabetes even without overt pancreas agenesis.

References

• Diabetes • 2010 • A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. PMID:20009086

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