Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man

Abstract

Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development. We identified homozygous mutations in 7 different genes in 11 unrelated patients and show that NKX2-2 and MNX1 are etiological genes for neonatal diabetes, thus confirming their key role in development of the human pancreas. The similar phenotype of the patients with recessive mutations and mice with inactivation of a transcription factor gene support there being common steps critical for pancreatic development and validate the use of rodent models for beta cell development.

Graphical abstract

Figure 1

NKX2-2 and MNX1 Mutations in Four Families with Neonatal Diabetes (A) Partial pedigrees of two families in which NKX2-2 mutations were identified. Below each pedigree is an electropherogram depicting the homozygous mutation identified in each proband. N/A, not available. (B) Partial pedigrees of two families with MNX1 mutations. Below each pedigree is an electropherogram depicting the homozygous mutation identified in each proband. (C) The highly conserved sequence of the homeobox domain within MNX1 is provided for various species. An arrow points to the residues found to be mutated in the two probands with permanent neonatal diabetes. See also Figure S1.