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: J A Ibdah, I Tein, C Dionisi-Vici, M J Bennett, L IJlst, B Gibson, R J Wanders, A W Strauss
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 102 Issue 6 Pg. 1193-9 (Sep 15 1998) ISSN: 0021-9738 [Print] United States
• PMID: 9739053 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fatty Acids
• Multienzyme Complexes
• RNA, Messenger
• Mitochondrial Trifunctional Protein

Topics

• Adolescent
• Child
• Chronic Disease
• Exons
• Fatty Acids (metabolism)
• Genotype
• Hereditary Sensory and Motor Neuropathy (genetics)
• Heterozygote
• Homozygote
• Humans
• Male
• Mitochondrial Myopathies (genetics)
• Mitochondrial Trifunctional Protein
• Multienzyme Complexes (deficiency, genetics)
• Mutation
• Pedigree
• Phenotype
• Polymorphism, Single-Stranded Conformational
• RNA, Messenger (genetics)
• Sequence Analysis, DNA