Premium
Ancestral mutations may cause a significant proportion of GCK‐MODY
Author(s) -
Dusatkova Petra,
Pruhova Stepanka ,
Borowiec Maciej,
Vesela Klara,
Antosik Karolina ,
Lebl Jan,
Mlynarski Wojciech,
Cinek Ondrej
Publication year - 2012
Publication title -
pediatric diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.678
H-Index - 75
eISSN - 1399-5448
pISSN - 1399-543X
DOI - 10.1111/j.1399-5448.2011.00845.x
Subject(s) - haplotype , genetics , founder effect , mutation , biology , maturity onset diabetes of the young , genotype , gene , population , glucokinase , lineage (genetic) , medicine , environmental health
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.Glu 40 L ys (21 apparently unrelated families), p.Leu 315 H is (15 families), p.Gly 318 A rg (26 families), and p.Val 33 A la (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.Glu 40 L ys mutation was associated with an 11‐marker long conserved haplotype, the p.Leu 315 H is mutation was associated with a 7‐marker haplotype, and the p.Gly 318 A rg 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.Val 33 A la, 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.