Fig. 1.

Detection of a non-conservative heterozygous mutation in AKT2 that co-segregates with severe insulin resistance. (A) Direct sequencing of genomic DNA from the proband, subject (iii)/1 (right) and a control subject (left). Asterisk indicates the heterozygous G to A substitution that produces H274. (B) Location of R274 in relation to known functional domains and phosphorylation sites required for activation of AKT2. (C) R274 (in red and marked *) is highly conserved across different AKT isoforms and diverse species. (D) Family pedigree demonstrating co-segregation of clinical phenotype (also see Table S1) with the R274H mutation. All family members heterozygous for the mutation (+/-) are hyperinsulinemic and 3 of 4 have diabetes mellitus. All wild type subjects (+/+) are normoinsulinemic and non-diabetic. Red denotes fasting hyperinsulinemia. Green denotes Diabetes Mellitus.