ALPS and my FAS mutation

What ALPS is

Autoimmune lymphoproliferative syndrome (ALPS) is a rare condition of the immune system. When the body fights an infection, it makes far more white blood cells than it needs. Afterward, the extras are told to self-destruct. The order comes from a signal called FAS ligand, and it’s received by a protein on the cell’s surface called FAS. When FAS doesn’t work properly, the extra immune cells don’t die off. They build up in the spleen and lymph nodes, and the immune system can turn on the body’s own blood cells.

That’s why the most common signs of ALPS are an enlarged spleen, swollen lymph nodes, and low blood counts.

Where my mutation is

FAS works like a doorbell. One end sits outside the cell and catches the self-destruct signal. The other end sits inside the cell and passes the message along. The best-studied ALPS mutations are in that inside part, called the death domain. About half of FAS mutations in ALPS are somewhere else.

Mine is on the outside, in the exact part that catches the signal. It changes one building block of the protein, at position 111. An NIH study that tested this same change found that cells carrying it have nearly normal amounts of FAS on their surface. The problem is that FAS barely grabs the signal. In lab tests, the changed protein couldn’t pass the message on at all, and it also blocked the healthy copy made by my other gene, about as strongly as the death-domain mutations do. The study found it in four unrelated people.

One of the scientists on that study is my own doctor at the NIH.

Why location matters

In the same study, families with mutations in the outside part of FAS were more likely to have relatives who carried the mutation with mild symptoms or none at all. Doctors call this lower penetrance: having the mutation doesn’t guarantee getting sick, and severity can vary a lot, even within one family. That finding was for the outside-the-cell group as a whole. My specific change wasn’t scored on its own, and in the lab it acted more like the stronger, inside mutations.

My details

• Gene: FAS
• Change: c.332A>G, p.His111Arg (often written H111R), in exon 3
• Copies: one (heterozygous)
• Confirmed by: the NIH Clinical Center, June 2015
• Why I was tested: an enlarged spleen, swollen lymph nodes, low blood counts and recurring mouth ulcers

My blood counts since 2012 are charted on the My story page.

Sources

• Hsu AP, Dowdell KC, Davis J, Niemela JE, Anderson SM, Shaw PA, Rao VK, Puck JM. “Autoimmune lymphoproliferative syndrome due to FAS mutations outside the signal-transducing death domain: molecular mechanisms and clinical penetrance.” Genetics in Medicine 14(1):81–89, 2012.
• Kuehn HS et al. “FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome.” Journal of Immunology 186:6035–6043, 2011. (Cited in my NIH genetic report.)