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APOE p.Leu167del mutation in familial hypercholesterolemia
Zuhier Awan1, Hong Y Choi, Nathan Stitziel
1The Research Institute of the McGill University Health Centre, Faculty of Medicine, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, QC H3A 1A1, Canada; Institut de Recherches Cliniques (IRCM) Affiliated to Université de Montréal, 110 Pine Avenue West, Montréal, QC, Canada.
Atherosclerosis
|November 26, 2013
Summary
Autosomal dominant hypercholesterolemia (ADH) can be caused by mutations in the apolipoprotein E (APOE) gene. This study identified a novel APOE mutation, expanding the known genetic causes of ADH.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Biochemistry
Background:
- Autosomal dominant hypercholesterolemia (ADH) is a genetic disorder characterized by high LDL cholesterol levels.
- Mutations in LDLR, APOB, and PCSK9 genes are known causes, but many ADH cases remain genetically unexplained.
- This suggests additional genetic etiologies for ADH.
Observation:
- A proband of Italian origin presented with premature myocardial infarction and severe hypercholesterolemia.
- Clinical examination revealed tendinous xanthomas and xanthelasmas.
- Biochemical analysis showed markedly elevated total and LDL cholesterol, with normal HDL cholesterol and triglycerides.
Findings:
- Standard genetic sequencing did not reveal mutations in known ADH-related genes (LDLR, PCSK9, LDLRAP1, APOB).
- Exome sequencing identified a novel in-frame deletion in the apolipoprotein E (APOE) gene (APOE Leu167del).
- Computational analysis confirmed the deleterious impact of the APOE Leu167del mutation on protein structure within the receptor-binding domain.
Implications:
- This study confirms APOE gene mutations as a cause of ADH, representing the fourth identified genetic locus.
- The findings highlight the importance of including APOE gene screening in the diagnostic workup for ADH.
- Expanding the genetic understanding of ADH can improve diagnosis and management of affected individuals.
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