title: Ancestral mutations may cause a significant proportion of GCK-MODY.
abstract: BACKGROUND
  Although the literature indicates that ancestral mutations in the glucokinase (GCK) gene are rare, we have detected a high frequency of four prevalent mutations that together are responsible for over one third of the GCK mutations in our Czech National Register of monogenic diabetes. Therefore, we studied their potential ancestral origin in our and neighbouring Polish populations.
  
  
  METHODS
  We analysed the lineage of four mutations in the GCK gene - p.Glu40Lys (21 apparently unrelated families), p.Leu315His (15 families), p.Gly318Arg (26 families), and p.Val33Ala (10 families) - using genotypes of 16 single nucleotide polymorphisms that span a 14 Mb region around the gene. Haplotypes were reconstructed using Phase and Haploview programmes, and their age was estimated using dmle+.
  
  
  RESULTS
  We found strong evidence that supports ancestral origin of three of the four mutations: the p.Glu40Lys mutation was associated with an 11-marker long conserved haplotype, the p.Leu315His mutation was associated with a 7-marker haplotype, and the p.Gly318Arg mutation was associated with an 8-marker haplotype. None of these haplotypes were detected in the general population with a frequency >0.5%. The ages of the mutations were roughly estimated to be between 82 and 110 generations old (95% credible sets 65-151). The fourth prevalent mutation, p.Val33Ala, lacked statistically significant evidence for the founder effect, although there were some indications for its common origin.
  
  
  CONCLUSIONS
  The large proportion of families carrying three ancestral mutations in GCK indicates that the previously assumed rarity of the founder effect with regard to GCK-maturity onset diabetes of the young (MODY) should be reconsidered.
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Dusatkova
authors.forename: Stepanka
authors.initials: S
authors.lastname: Pruhova
authors.forename: Maciej
authors.initials: M
authors.lastname: Borowiec
authors.forename: Klara
authors.initials: K
authors.lastname: Vesela
authors.forename: Karolina
authors.initials: K
authors.lastname: Antosik
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mlynarski
authors.forename: Ondrej
authors.initials: O
authors.lastname: Cinek
mesh_terms: D000293:Adolescent; D000328:Adult; D018153:Czech Republic / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005190:Family; D005260:Female; D018703:Founder Effect; D005838:Genotype; D005941:Glucokinase / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D011044:Poland / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D055815:Young Adult
chemical_list: D005941:Glucokinase