Familial Hypercholesterolemia (FH) is a common inherited condition causing extremely high levels of low-density lipoprotein (LDL) cholesterol, often called “bad cholesterol,” from birth. FH impairs the body’s ability to clear LDL cholesterol from the bloodstream, leading to its dangerous accumulation in the arteries. Understanding the precise genetic nature of FH guides diagnosis, risk assessment for family members, and the specialized management required to prevent premature heart disease. FH is caused by a small-scale change in the genetic code, known as a gene mutation, not a large-scale chromosomal abnormality.
Genetic Mutation Versus Chromosomal Abnormality
The distinction between a genetic mutation and a chromosomal abnormality centers on the scale of the change within the human genome. Chromosomal abnormalities involve large-scale issues, such as having an extra or missing chromosome, or substantial structural rearrangements like duplications or deletions of large segments. These macro-level changes often affect hundreds or thousands of genes simultaneously, leading to conditions like Down Syndrome, caused by an extra copy of chromosome 21.
A gene mutation is a micro-level change, typically a permanent alteration in the DNA sequence of a single gene. This involves the substitution, insertion, or deletion of a few base pairs within the gene’s code, which changes the instructions for making a specific protein. FH falls into this category because the physical structure and number of chromosomes are normal in affected individuals. The problem lies in the specific coding sequence of a single gene responsible for cholesterol metabolism.
The Key Genes Responsible for FH
The vast majority of FH cases are linked to mutations in one of three main genes: LDLR, APOB, and PCSK9. The LDLR gene is the most common site of mutation, accounting for approximately 85% to 90% of genetically confirmed FH cases. This gene provides instructions for making the Low-Density Lipoprotein Receptor protein, found primarily on the surface of liver cells.
The LDL receptor normally binds to LDL particles circulating in the blood and internalizes them into the liver cell for removal. When a mutation occurs in the LDLR gene, the resulting receptor protein is non-functional, reduced in number, or absent from the cell surface, impairing cholesterol clearance.
A second gene, APOB, codes for Apolipoprotein B-100, the specific protein on the surface of the LDL particle that the LDL receptor recognizes and binds to. Mutations in APOB prevent this binding process, effectively making the LDL particle invisible to the receptor.
The third gene, PCSK9, is less commonly mutated but plays an important regulatory role. The protein produced by PCSK9 binds to the LDL receptor on the cell surface and targets it for degradation inside the cell. A “gain-of-function” mutation in PCSK9 leads to an overactive protein that destroys too many LDL receptors, reducing the liver’s ability to clear cholesterol.
How FH is Inherited and Expressed
FH is typically an Autosomal Dominant disorder, meaning a person only needs to inherit one copy of the mutated gene from one parent to develop the condition. This inheritance pattern gives each child of an affected parent a 50% chance of inheriting the mutation. This most common form is known as Heterozygous FH (HeFH) and is characterized by significantly elevated LDL cholesterol levels.
A much rarer and more severe form is Homozygous FH (HoFH), which occurs when a child inherits a mutated copy of the gene from both parents. HoFH is associated with extremely high LDL cholesterol levels, often reaching four times the normal level. This leads to the premature development of cardiovascular disease, sometimes in early childhood. The severity of the condition is directly related to the number of functional gene copies and the resulting level of LDL receptor activity.
The Mechanism of High Cholesterol Accumulation
Regardless of which of the three main genes is affected, the ultimate consequence is a failure to effectively clear LDL cholesterol from the bloodstream. Liver cells are responsible for removing approximately 70% of the LDL particles from circulation, a process that relies almost entirely on functional LDL receptors. When a mutation impairs the receptor, the LDL particles remain in the blood for an extended period.
This persistent elevation of LDL cholesterol from birth allows the particles to penetrate the walls of arteries, where they accumulate and initiate atherosclerosis. This buildup forms fatty plaques that narrow the blood vessels, which can eventually lead to heart attacks or strokes at an unusually young age. The genetic defect translates into a functional impairment in cholesterol recycling, leading to the lifelong accumulation of “bad” cholesterol in the body.