title: Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency.
abstract: OBJECTIVE
  Recessive PDX1 (IPF1) mutations are a rare cause of pancreatic agenesis, with three cases reported worldwide. A recent report described two cousins with a homozygous hypomorphic PDX1 mutation causing permanent neonatal diabetes with subclinical exocrine insufficiency. The aim of our study was to investigate the possibility of hypomorphic PDX1 mutations in a large cohort of patients with permanent neonatal diabetes and no reported pancreatic hypoplasia or exocrine insufficiency.
  
  
  METHODS
  PDX1 was sequenced in 103 probands with isolated permanent neonatal diabetes in whom ABCC8, KCNJ11 and INS mutations had been excluded.
  
  
  RESULTS
  Sequencing analysis identified biallelic PDX1 mutations in three of the 103 probands with permanent neonatal diabetes (2.9%). One proband and his affected brother were compound heterozygotes for a frameshift and a novel missense mutation (p.A34fsX191; c.98dupC and p.P87L; c.260C>T). The other two probands were homozygous for novel PDX1 missense mutations (p.A152G; c.455C>G and p.R176Q; c.527G>A). Both mutations affect highly conserved residues located within the homeobox domain. None of the four cases showed any evidence of exocrine pancreatic insufficiency, either clinically, or, where data were available, biochemically. In addition a heterozygous nonsense mutation (p.C18X; c.54C>A) was identified in a fourth case.
  
  
  CONCLUSIONS
  This study demonstrates that recessive PDX1 mutations are a rare but important cause of isolated permanent neonatal diabetes in patients without pancreatic hypoplasia/agenesis. Inclusion of the PDX1 gene in mutation screening for permanent neonatal diabetes is recommended as a genetic diagnosis reveals the mode of inheritance, allows accurate estimation of recurrence risks and confirms the requirement for insulin treatment.
authors: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors: E
authors: E
authors: De Franco
authors: C
authors: C
authors: Shaw-Smith
authors: S E
authors: SE
authors: Flanagan
authors: E L
authors: EL
authors: Edghill
authors: J
authors: J
authors: Wolf
authors: V
authors: V
authors: Otte
authors: F
authors: F
authors: Ebinger
authors: P
authors: P
authors: Varthakavi
authors: T
authors: T
authors: Vasanthi
authors: S
authors: S
authors: Edvardsson
authors: A T
authors: AT
authors: Hattersley
authors: S
authors: S
authors: Ellard
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005088:Exocrine Glands / Q000503:physiopathology*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D020125:Mutation, Missense; D010179:Pancreas / Q000002:abnormalities; D010182:Pancreatic Diseases / Q000151:congenital / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein