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

Sarah E. Flanagan, Elisa De Franco, Hana Lango Allen, Michele Zerah, Majedah M. Abdul-Rasoul, Julie A. Edge, Helen Stewart, Elham Alamiri, Khalid Hussain, Sam Wallis, Liat De Vries, Oscar Rubio-Cabezas, Jayne A.L. Houghton, Emma L. Edghill, Ann Marie Patch, Sian Ellard, Andrew T. Hattersley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)146-154
Number of pages9
JournalCell Metabolism
Volume19
Issue number1
DOIs
StatePublished - 7 Jan 2014

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