2.1. Alzheimer disease

More than 150 PSEN1 gene mutations have been identified in patients with early-onset Alzheimer disease, a degenerative brain condition that begins before age 65. Mutations in the PSEN1 gene are the most common cause of early-onset Alzheimer disease, accounting for up to 70 percent of cases.

Almost all PSEN1 gene mutations change single building blocks of DNA (nucleotides) in a particular segment of the PSEN1 gene. These mutations result in the production of an abnormal presenilin 1 protein. Defective presenilin 1 interferes with the function of the γ-secretase complex, which alters the processing of APP and leads to the overproduction of a longer, toxic version of amyloid-β peptide. Copies of this protein fragment stick together and build up in the brain, forming clumps called amyloid plaques that are a characteristic feature of Alzheimer disease. A buildup of toxic amyloid-β peptide and the formation of amyloid plaques likely lead to the death of neurons and the progressive signs and symptoms of this disorder.

2.2. Hidradenitis suppurativa

At least one mutation in the PSEN1 gene has been found to cause hidradenitis suppurativa, a chronic skin disease characterized by recurrent boil-like lumps (nodules) under the skin that develop in hair follicles. The nodules tend to become inflamed and painful, and they produce significant scarring as they heal.

The identified mutation deletes a single DNA building block (nucleotide) from the PSEN1 gene, written as 725delC. This genetic change reduces the amount of functional presenilin 1 produced in cells, so less of this protein is available to act as part of the γ-secretase complex. The resulting shortage of normal γ-secretase impairs cell signaling pathways, including Notch signaling. Although little is known about the mechanism, studies suggest that abnormal Notch signaling may promote the development of recurrent nodules in hair follicles and trigger inflammation in the skin.

Studies suggest that the PSEN1 gene mutation that causes hidradenitis suppurativa has a different effect on γ-secretase function than the mutations that cause early-onset Alzheimer disease. These differences may explain why no single PSEN1 gene mutation has been reported to cause the signs and symptoms of both diseases.