Glycerol kinase deficiency: Evidence for complexity in a single gene disorder

Glycerol kinase deficiency (GKD) occurs as part of an Xp21 contiguous gene syndrome or as isolated GKD. The isolated form can be either symptomatic wi th episodic metabolic and central nervous system (CNS) decompensation or as ymptomatic with hyperglycerolemia and glyceroluria only. To better understa nd the pathogenesis of isolated GKD, we sought individuals with point mutat ions in the GK coding region and measured their GK enzyme activities. We id entified six individuals with missense mutations: four (N288D, A305V, M428T , and Q438R) among males who were asymptomatic and two (D198G, R405Q) in in dividuals who were symptomatic. GK activity measured in lymphoblastoid cell lines or fibroblasts was similar for the symptomatic and the asymptomatic individuals. Mapping of the individuals' missense mutations to the three-di mensional structure of Escherichia coli GK revealed that the symptomatic in dividuals' mutations are in the same region as a subset of the mutations am ong the asymptomatic individuals, adjacent to the active-site cleft. We con clude that, like many other disorders, GK genotype does not predict GKD phe notype. We hypothesize that the phenotype of an individual with GKD is a co mplex trait influenced by additional, independently inherited genes.