Analysis of Transcription Factors Key for Mouse Pancreatic Development Establishes NKX2-2 and MNX1 Mutations As Causes of Neonatal Diabetes in Man

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2014 Jan 14

PMID 24411943

Citations 71

Authors

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

Affiliations

Soon will be listed here.

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.

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