Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY)

Abstract

Maturity-onset diabetes of the young (MODY) resulting from mutations in the glucokinase

Detection of glucokinase gene defects in non-obese Japanese children diagnosed with diabetes by school medical examinations

“…Among Caucasian tribes, the GCK gene defect is known to be important in the cause of MODY, so called MODY2, and many mutations have been reported from several European ethnic origins [2][3][4][5][6]. In contrast, adult-based sample collection in Japan suggested that mutation in GCK is rare in MODY, and some cases have obese subjects tend to avoid further medical examination until the appearance of nasty subjective symptoms such as excessive urination.…”

The previously reported T342P GCK missense variant is not a pathogenic mutation causing MODY

“…Thus, taken together with structural modelling and functional characterisation, the results of in silico analyses are consistent with the clinical data, which shows that the GCK T342P substitution is benign and not the cause of diabetes in the individuals reported. Therefore, the variant described in the original family was coincidental and was not causative of their diabetes [4].…”

“…Surprisingly, of the 29 single nucleotide polymorphisms (SNPs) described within the coding region of the pancreatic isoform, only one (D4N) results in a missense substitution [3]. T342P (c.1024A>C; p.Thr342Pro) has previously been reported as a pathogenic mutation following its identification in a single family (family SQ) [4]. We now report a second, unrelated family (family GB) with this variant and our clinical and functional studies suggest that T342P should be re-classified as a rare, non-pathogenic variant.…”

“…Threedimensional modelling in PyMol indicated the T342P substitution was unlikely to cause perturbation to the protein structure. A previous study reported the GCK T342P mutation as a pathogenic loss-of-function MODY mutation [4]. At that time, bioinformatic prediction software was not widely available and it was believed that all missense variants in GCK were likely to be pathogenic.…”

Common variants in MODY genes increase the risk of gestational diabetes mellitus

“…Women with mutations in GCK [12][13][14][15][16][17] or HNF1A [16,18] often present with GDM. In addition, mutations in IPF1 have been reported in women with GDM [16,19].…”