Glycerol as a correlate of impaired glucose tolerance: dissection of a complex system by use of a simple genetic trait.

Glycerol kinase (GK) represents the primary entry of glycerol into glucose and triglyceride metabolism.
Impaired glucose tolerance (IGT) and hypertriglyceridemia are associated with an increased risk of diabetes mellitus and cardiovascular disease.
The relationship between glycerol and the risk of IGT, however, is poorly understood.
We therefore undertook the study of fasting plasma glycerol levels in a cohort of 1, 056 unrelated men and women of French-Canadian descent.
Family screening in the initial cohort identified 18 men from five families with severe hyperglycerolemia (values above 2. 0 mmol/liter) and demonstrated an X-linked pattern of inheritance.
Linkage analysis of the data from 12 microsatellite markers surrounding the Xp21. 3 GK gene resulted in a peak LOD score of 3. 46, centered around marker DXS8039. In addition, since all of the families originated in a population with a proven founder effect-the Saguenay Lac-St. -Jean region of Quebec-a common disease haplotype was sought.
Indeed, a six-marker haplotype extending over a region of 5. 5 cM was observed in all families.
Resequencing of the GK gene in family members led to the discovery of a N288D missense mutation in exon 10, which resulted in the substitution of a highly conserved asparagine residue by a negatively charged aspartic acid.

