A rare STAP1 mutation incompletely associated with familial hypercholesterolemia

Area of Science:

• Genetics
• Cardiovascular Medicine
• Molecular Biology

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL cholesterol levels.
• Mutations in LDLR, APOB, and PCSK9 genes are common causes of FH.
• Emerging research suggests the STAP1 gene may also play a role in FH pathogenesis.

Observation:

• A 56-year-old male with a history of hypercholesterolemia since age 34 and a myocardial infarction at age 55 was studied.
• Next-generation sequencing (NGS) excluded mutations in known FH-related genes (LDLR, APOB, LDLRAP1, PCSK9).
• A heterozygous missense variant (rs199787258, c.526C>T; p.Pro176Ser) in the STAP1 gene was identified in the patient.

Findings:

• The identified STAP1 p.Pro176Ser variant was also found in hypercholesterolemic siblings but not in the patient's offspring.
• Bioinformatics analysis predicted this STAP1 variant as the most damaging among those linked to FH.
• This case confirms and expands the association between STAP1 variants and familial hypercholesterolemia.

Implications:

• STAP1 variants represent a novel genetic cause of familial hypercholesterolemia.
• The STAP1 protein is implicated in a critical signaling pathway influencing cholesterol homeostasis.
• Further research into STAP1's role could lead to new diagnostic and therapeutic strategies for FH.