title: Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency.
abstract: Mitochondrial trifunctional protein (MTP) deficiency is a rare inherited metabolic disorder of mitochondrial fatty acid oxidation. We newly characterized three novel mutations in 2 Japanese patients with MTP deficiency, and investigated the clinical and molecular aspects of 5 Japanese patients including 3 previously reported cases. Herein, we describe the characterization of four missense mutations, R214C, H346R, R411K, and V422G, in the HADHB gene, which have been identified in Japanese patients, employing a newly developed, sensitive transient expression analysis. Co-transfection of wild-type HADHA and HADHB cDNAs in SV40-transfected fibroblasts from a MTP-deficient patient yielded sufficient enzyme activity to evaluate low-level residual enzyme activity, using two incubation temperatures of 30 degrees C and 37 degrees C. At 30 degrees C, residual enzyme activity was higher than that at 37 degrees C in V422G, R214C, and R411K. However, H346R, which was seen in the most severe case, showed no enzyme activity at both temperatures. Our results demonstrate that a defect of HADHB in MTP deficiency is rather common in Japanese patients, and the mutational spectrum is heterogeneous. The present findings showed that all missense mutations in this study were disease-causing. Although the number of patients is still limited, it is suggested that the phenotype is correlated with the genotype and a combination of two mutant alleles of the HADHB gene in MTP deficiency.
authors.affiliation: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Japan.
authors.forename: Jamiyan
authors.initials: J
authors.lastname: Purevsuren
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukao
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Hironori
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Mushimoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D000293:Adolescent; D044466:Asian People / Q000235:genetics*; D015153:Blotting, Western; D002457:Cell Extracts; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics; D063991:Mitochondrial Trifunctional Protein; D063992:Mitochondrial Trifunctional Protein, alpha Subunit; D063993:Mitochondrial Trifunctional Protein, beta Subunit; D009097:Multienzyme Complexes / Q000172:deficiency* / Q000235:genetics; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D014162:Transfection
chemical_list: D002457:Cell Extracts; D018076:DNA, Complementary; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D050505:Mutant Proteins; C576205:HADHA protein, human; D063992:Mitochondrial Trifunctional Protein, alpha Subunit; D000102:Acetyl-CoA C-Acyltransferase; C576206:HADHB protein, human; D063991:Mitochondrial Trifunctional Protein; D063993:Mitochondrial Trifunctional Protein, beta Subunit