title: Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals.
abstract: BACKGROUND
  Mutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene.
  
  
  METHODS
  Location and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion.
  
  
  RESULTS
  The 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5-16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22).
  
  
  CONCLUSIONS
  Complete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age.
authors.affiliation: Department of Pediatric Endocrinology and Diabetes, Charité Children's Hospital, Universitätsmedizin Berlin, Charité Campus Virchow, Augustenburger Platz 1, D-13353 Berlin, Germany. klemens.raile@charite.de
authors.forename: Klemens
authors.initials: K
authors.lastname: Raile
authors.forename: Michele
authors.initials: M
authors.lastname: O'Connell
authors.forename: Angela
authors.initials: A
authors.lastname: Galler
authors.forename: George
authors.initials: G
authors.lastname: Werther
authors.forename: Peter
authors.initials: P
authors.lastname: Kühnen
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Oliver
authors.initials: O
authors.lastname: Blankenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D003241:Consanguinity; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005190:Family; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D055815:Young Adult
chemical_list: D007328:Insulin