title: 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.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Franco
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Hana
authors.initials: H
authors.lastname: Lango Allen
authors.affiliation: Presbyterian Medical Group, Albuquerque, NM 87106, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Zerah
authors.affiliation: Faculty of Medicine, Department of Pediatrics, Kuwait University, Safat 13110, Kuwait.
authors.forename: Majedah M
authors.initials: MM
authors.lastname: Abdul-Rasoul
authors.affiliation: Oxford Children's Hospital, Headington, Oxford OX3 9DU, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Edge
authors.affiliation: Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.affiliation: Al Qassimi Hospital, Sharjah 3500, United Arab Emirates.
authors.forename: Elham
authors.initials: E
authors.lastname: Alamiri
authors.affiliation: 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.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.affiliation: Neonatal Unit, Bradford Royal Infirmary, Bradford BD9 6RJ, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Wallis
authors.affiliation: 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.
authors.forename: Liat
authors.initials: L
authors.lastname: de Vries
authors.affiliation: 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.
authors.forename: Oscar
authors.initials: O
authors.lastname: Rubio-Cabezas
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Jayne A L
authors.initials: JA
authors.lastname: Houghton
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Edghill
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK. Electronic address: a.t.hattersley@exeter.ac.uk.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D002675:Child, Preschool; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D005260:Female; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D010179:Pancreas / Q000254:growth & development* / Q000378:metabolism*; D010641:Phenotype; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D029961:Zebrafish Proteins
chemical_list: D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C490003:MNX1 protein, human; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; C084059:Hb9 protein, mouse