Homozygous mutations in the pancreas-specific transcription factor 1A gene (PTF1A) lead to pancreatic agenesis associated with cerebellar agenesis, affected individuals are born with permanent neonatal diabetes mellitus. PTF1A is important for pancreatic outgrowth in early embryogenesis and cerebellar formation. Low insulin levels can be detected in the blood of patients with these homozygous mutations. The source of insulin production has not been elucidated in humans; but in mice, insulin is thought to be secreted by scattered ectopic beta-cells in the spleen (PMID:24843749). Early in pancreatic development, active PTF1a requires interaction with RBPJ, the vertebrate Suppressor of Hairless, within a stable trimeric DNA-binding complex (PTF1A-RBPJ complex). Later, as acinar cell development begins, RBPJ is swapped for RBPJL, the constitutively active, pancreas-restricted paralog of RBPJ (PTF1A-RBPJL complex) (PMID:17938243).
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