ACE

Mutations in the ACE gene are the most common cause of a severe kidney disorder called renal tubular dysgenesis; at least 33 ACE gene mutations have been found in people with this disorder. Renal tubular dysgenesis is characterized by abnormal kidney development before birth, the inability to produce urine (anuria), and severe low blood pressure (hypotension). These problems result in a reduction of amniotic fluid (oligohydramnios), which leads to a set of birth defects known as the Potter sequence.

Renal tubular dysgenesis can be caused by mutations in both copies of any of the genes involved in the renin-angiotensin system. The ACE gene mutations that cause this disorder prevent the production of functional angiotensin-converting enzyme, which impairs the formation of angiotensin II and results in a nonfunctional renin-angiotensin system. Without this system, the kidneys cannot control blood pressure. Because of low blood pressure, the flow of blood is reduced (hypoperfusion), and the body does not get enough oxygen during fetal development. As a result, kidney development is impaired, leading to the features of renal tubular dysgenesis.

A certain variation in the ACE gene has been associated with increased risk of several conditions, including stroke and complications of diabetes. This genetic variation, called the ACE I/D polymorphism, involves a region of DNA that spans 287 DNA building blocks (nucleotides). One variant of the ACE gene includes this region; it is called the insertion, or I, allele. Another variant is missing this region of DNA and is called the deletion, or D, allele. Because people have two copies of each gene, each individual can have two I alleles (II), two D alleles (DD), or one allele of each (ID). The DD pattern is associated with higher levels of angiotensin-converting enzyme than the II pattern. The ID pattern is associated with intermediate levels.

People with the DD pattern of alleles have an increased risk of stroke. Stroke can be caused by a lack of blood flow to the brain (ischemic stroke) or bleeding in the brain (hemorrhagic stroke or intracerebral hemorrhage). Susceptibility to both types is associated with the ACE gene variation. However, many genetic and environmental risk factors likely contribute to this complex condition.

In people with type 1 diabetes or type 2 diabetes, the DD pattern of alleles is associated with an increased risk of developing a kidney disorder called diabetic nephropathy. Damage to the kidneys caused by this condition worsens over time and can lead to kidney failure.