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Published on: October 9, 2014
Two alpha subunit donor splice site mutations cause human trifunctional protein deficiency
J C Brackett1, H F Sims, P Rinaldo
1Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
The Journal of Clinical Investigation
|May 1, 1995
Summary
Trifunctional protein deficiency, crucial for fatty acid breakdown, was molecularly characterized. Two splice site mutations caused exon skipping, leading to complete protein loss and severe infant health issues.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Human trifunctional protein is essential for mitochondrial fatty acid beta-oxidation.
- Deficiency causes severe conditions like sudden infant death and cardiomyopathy.
Observation:
- A patient with neonatal presentation and sudden death showed a complete loss of trifunctional protein.
- Analysis revealed a universal deletion of exon 3 in the alpha subunit mRNA.
Findings:
- The patient had compound heterozygous mutations in the 5' donor splice site of exon 3.
- These mutations (G to A at +1, A to G at +3) caused exon 3 skipping and premature termination.
- This resulted in undetectable alpha subunit protein and complete loss of trifunctional protein activity.
Implications:
- This study provides the initial molecular characterization of trifunctional protein deficiency.
- Understanding these mutations aids in diagnosing and potentially managing this severe genetic disorder.
- Highlights the critical role of splicing in maintaining functional enzyme complexes.
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