Genomic and Mutational Analysis of the Mitochondrial Trifunctional Protein β-Subunit (HADHB) Gene in Patients with Trifunctional Protein Deficiency

Mitochondrial trifunctional protein (TP), an enzyme of β-oxidation, is a multienzyme complex composed of four molecules of the α-subunit (HADHA) containing the enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase domains and four molecules of theβ-subunit (HADHB) containing the 3-ketoacyl-CoA thiolase domain. An inborn error of this enzyme complex can cause sudden infant death syndrome, acute hepatic encephalopathy or liver failure, skeletal myo-pathy, or hypertrophic cardiomyopathy. TP deficiency is classified into two different biochemical pheno-types: one represents the existence of both subunits and the lack of only the 3-hydroxyacyl-CoA dehy-drogenase activity and the other represents the absence of both subunits and the lack of all three TP activities, although their clinical features are similar. We have identified two Japanese patients with this disorder. Three enzyme activities of TP were undetectable in fibroblasts from these two patients. We detected two mutations in the HADHB gene from two Japanese patients, an exonic single T insertion which created a new cryptic 5′ splice site and a G1331A transition (R411K). Patient 1 was a compound heterozygote, while patient 2 was a homozygote of a G1331A transition.