Homozygous mutations in PDX1 lead to pancreatic agenesis resulting in permanent neonatal diabetes and exocrine pancreatic insufficiency. Heterozygous mutations lead to a variable defect in insulin secretion and diabetes (MODY4) (PMID:23869298).
Mutation in the PDX1 gene is a rare cause of MODY (Fajans et al., 2001). In a consanguineous family, originally reported by Wright et al. (1993), in which an infant with pancreatic agenesis (260370) was homozygous for a ... Mutation in the PDX1 gene is a rare cause of MODY (Fajans et al., 2001). In a consanguineous family, originally reported by Wright et al. (1993), in which an infant with pancreatic agenesis (260370) was homozygous for a 1-bp deletion in the PDX1 gene (600733.0001), Stoffers et al. (1997) found that members heterozygous for this mutation had early-onset type II diabetes mellitus, which they designated MODY4. The expression of diabetes in this family may occur at later ages than in families with other types of MODY. In the course of expressing the mutant IPF1 protein (Stoffers et al., 1997) in eukaryotic cells, Stoffers et al. (1998) detected a second IPF1 isoform, recognized by C-terminal but not N-terminal-specific antisera. This isoform localized to the nucleus and retained DNA-binding functions. Internal translation initiating at an out-of-frame AUG accounted for the appearance of the protein. The reading frame crossed over to the wildtype IPF1 reading frame at the site of the point deletion just carboxy-proximal to the transactivation domain. Thus, the single mutated allele results in the translation of 2 IPF1 isoforms; the first consists of the N-terminal transactivation domain and is sequestered in the cytoplasm, and the second contains the C-terminal DNA-binding domain but lacks the transactivation domain. The C-terminal domain IPF1 isoform does not activate transcription and inhibits the transactivation functions of wildtype IPF1. This circumstance suggested that the mechanism of diabetes in individuals with this mutation may be not only reduced gene dosage but also a dominant-negative inhibition of transcription of the insulin gene and other beta-cell-specific genes regulated by the mutant IPF1. Thomas et al. (2009) reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene identified by Stoffers et al. (1997) (600733.0001) in a similar family. Thomas et al. (2009) suggested that the 2 families might be related. Fajans et al. (2010) identified a single 2.5-Mb region on chromosome 13 shared by a Michigan-Kentucky pedigree originally reported by Thomas et al. (2009) and a Virginia pedigree, originally reported by Wright et al. (1993), both of which carried the 1-bp deletion in PDX1. The size of the shared region suggested that the PDX1 frameshift mutation emerged in a recent ancestor common to both probands, and that a complex pedigree structure connected the 2 probands.