title: Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.
abstract: Human mitochondrial trifunctional protein (TFP) is a heterooctamer of four alpha- and four beta-subunits that catalyzes three steps in the beta-oxidation spiral of long-chain fatty acids. TFP deficiency causes a Reye-like syndrome, cardiomyopathy, or sudden, unexpected death. We delineated the molecular basis for TFP deficiency in two patients with a unique phenotype characterized by chronic progressive polyneuropathy and myopathy without hepatic or cardiac involvement. Single-stranded conformation variance and nucleotide sequencing identified all patient mutations in exon 9 of the alpha-subunit. One patient is homozygous for the T845A mutation that substitutes aspartic acid for valine at residue 246. The second patient is a compound heterozygote for the T914A that substitutes asparagine for isoleucine at residue 269 and a C871T that creates a premature termination at residue 255. Allele-specific oligonucleotide hybridization studies revealed undetectable levels of the mRNA corresponding to the mutant allele carrying the termination codon. This study suggests a novel genotype-phenotype correlation in TFP deficiency; that is, mutations in exon 9 of the alpha-subunit, which encodes a linker domain between the NH2-terminal hydratase and the COOH-terminal 3-hydroxyacyl-CoA dehydrogenase, result in a unique neuromuscular phenotype.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Ibdah
authors.forename: I
authors.initials: I
authors.lastname: Tein
authors.forename: C
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: M J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: L
authors.initials: L
authors.lastname: IJlst
authors.forename: B
authors.initials: B
authors.lastname: Gibson
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: A W
authors.initials: AW
authors.lastname: Strauss
mesh_terms: D000293:Adolescent; D002648:Child; D002908:Chronic Disease; D005091:Exons; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D017240:Mitochondrial Myopathies / Q000235:genetics*; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D005227:Fatty Acids; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D063991:Mitochondrial Trifunctional Protein