Learning From Molecular Genetics
Novel Insights Arising From the Definition of Genes for Monogenic and Type 2 Diabetes
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
- 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
- 3Diabetes Genetics, Peninsula Medical School, Exeter, U.K
- Corresponding authors: Andrew T. Hattersley, andrew.hattersley{at}pms.ac.uk, and Mark I. McCarthy, mark.mccarthy{at}drl.ox.ac.uk
Genetic factors for many decades have been known to play a critical role in the etiology of diabetes, but it has been only recently that the specific genes have been identified. The identification of the underlying molecular genetics opens the possibility for understanding the genetic architecture of clinically defined categories of diabetes, new biological insights, new clinical insights, and new clinical applications. This article examines the new insights that have arisen from defining the etiological genes in monogenic diabetes and the predisposing polymorphisms in type 2 diabetes.
MONOGENIC DIABETES
Defining monogenic diabetes genes by candidate gene and positional cloning approaches.
There has been rapid progress in defining the etiological genes for monogenic diabetes reflecting the relative simplicity of gene discovery in single gene disorders. The candidate gene approach has been remarkably successful in defining monogenic genes; this reflects that key rate-limiting steps in insulin secretion and action are known, and severe mutations affecting these proteins will result in β-cell dysfunction or insulin resistance. Examples of this approach include the genes encoding insulin (1), glucokinase (2,3), the two ATP-sensitive K+ channel (KATP channel) subunits Kir6.2 (4) and SUR1 (5,6), peroxisome proliferator–activated receptor (PPAR)γ (7), and the insulin receptor (8). Finding human subjects with mutations in these candidate genes has allowed confirmation of a critical role in humans of the encoded protein, helped define structure and function of the protein, and allowed confirmation of the associated pathophysiology (e.g., abnormal glucose sensing in glucokinase mutations) (9), but it has not led to the identification of novel pathways in glucose homeostasis.
Completely unexpected critical pathways for insulin secretion and action have resulted from the positional cloning of novel monogenic diabetes genes. The most striking example was the identification of HNF1A, encoding the transcription factor hepatic nuclear factor (HNF)-1α, as the maturity-onset diabetes of the young (MODY) gene linked to 12q …
