GENOMIC AND MUTATIONAL ANALYSIS OF THE MITOCHONDRIAL TRIFUNCTIONAL PROTEIN BETA-SUBUNIT (HADHB) GENE IN PATIENTS WITH TRIFUNCTIONAL PROTEIN-DEFICIENCY

Mitochondrial trifunctional protein (TP), an enzyme of beta-oxidation, is a multienzyme complex composed of four molecules of the alpha-subu nit (HADHA) containing the enoyl-CoA hydratase and 3-hydroxyacyl-CoA d ehydrogenase domains and four molecules of the beta-subunit (HADHB) co ntaining the 3-ketoacyl-CoA thiolase domain. An inborn error of this e nzyme complex can cause sudden infant death syndrome, acute hepatic en cephalopathy or liver failure, skeletal myopathy, or hypertrophic card iomyopathy. TP deficiency is classified into two different biochemical phenotypes: one represents the existence of both subunits and the lac k of only the 3-hydroxyacyl-CoA dehydrogenase activity and the other r epresents the absence of both subunits and the lack of all three TP ac tivities, although their clinical features are similar. We have identi fied two Japanese patients with this disorder. Three enzyme activities of TP were undetectable in fibroblasts from these two patients. We de tected two mutations in the HADHB gene from two Japanese patients, an exonic single T insertion which created a new cryptic 5' splice site a nd a G1331A transition (R411K). Patient 1 was a compound heterozygote, while patient 2 was a homozygote of a G1331A transition.