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Cell Metab. 2014 Jan 7;19(1):146-54. doi: 10.1016/j.cmet.2013.11.021.

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

Author information

1
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
2
Presbyterian Medical Group, Albuquerque, NM 87106, USA.
3
Faculty of Medicine, Department of Pediatrics, Kuwait University, Safat 13110, Kuwait.
4
Oxford Children's Hospital, Headington, Oxford OX3 9DU, UK.
5
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK.
6
Al Qassimi Hospital, Sharjah 3500, United Arab Emirates.
7
London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, and The Institute of Child Health, University College London, London WC1N 1EH, UK.
8
Neonatal Unit, Bradford Royal Infirmary, Bradford BD9 6RJ, UK.
9
Institute of Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, PetahTikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 49202, Israel.
10
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK; Department of Paediatric Endocrinology, Hospital Infantil Niño Jesús, Madrid 28009, Spain.
11
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK. Electronic address: a.t.hattersley@exeter.ac.uk.

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.

PMID:
24411943
PMCID:
PMC3887257
DOI:
10.1016/j.cmet.2013.11.021
[Indexed for MEDLINE]
Free PMC Article

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