title: Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities.
abstract: OBJECTIVE
  NEUROD1 is expressed in both developing and mature beta-cells. Studies in mice suggest that this basic helix-loop-helix transcription factor is critical in the development of endocrine cell lineage. Heterozygous mutations have previously been identified as a rare cause of maturity-onset diabetes of the young (MODY). We aimed to explore the potential contribution of NEUROD1 mutations in patients with permanent neonatal diabetes.
  
  
  METHODS
  We sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology.
  
  
  RESULTS
  Two homozygous mutations in NEUROD1 (c.427_ 428del and c.364dupG) were identified in two patients. Both mutations introduced a frameshift that would be predicted to generate a truncated protein completely lacking the activating domain. Both patients had permanent diabetes diagnosed in the first 2 months of life with no evidence of exocrine pancreatic dysfunction and a morphologically normal pancreas on abdominal imaging. In addition to diabetes, they had learning difficulties, severe cerebellar hypoplasia, profound sensorineural deafness, and visual impairment due to severe myopia and retinal dystrophy.
  
  
  CONCLUSIONS
  We describe a novel clinical syndrome that results from homozygous loss of function mutations in NEUROD1. It is characterized by permanent neonatal diabetes and a consistent pattern of neurological abnormalities including cerebellar hypoplasia, learning difficulties, sensorineural deafness, and visual impairment. This syndrome highlights the critical role of NEUROD1 in both the development of the endocrine pancreas and the central nervous system in humans.
authors.affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK.
authors.forename: Oscar
authors.initials: O
authors.lastname: Rubio-Cabezas
authors.forename: Jayne A L
authors.initials: JA
authors.lastname: Minton
authors.forename: Iren
authors.initials: I
authors.lastname: Kantor
authors.forename: Denise
authors.initials: D
authors.lastname: Williams
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; C093970:NEUROD1 protein, human