FADD Gene

The FADD gene (FADD stands for "Fas Associated Via Death Domain") is a protein coding gene located on chromosome 11q13.3. The protein encoded by this gene is an adaptor molecule that interacts with various cell surface receptors and mediates cell apoptotic signals. Through its C-terminal death domain, this protein can be targeted by:

• TNFRSF6/Fas receptor
• tumor necrosis factor receptor, TNFRSF25
• TNFSF10/TRAIL receptor

recruited and is thus involved in death signaling initiated by these receptors. Interaction of this protein with the receptors exposes the N-terminal effector domain of the FADD protein, allowing it to recruit caspase-8 and thereby activate the cysteine protease cascade.

The FADD protein (apoptotic adaptor molecule) encoded by this gene associates caspase-8 (see belowCASP8)or caspase-10 )see below CASP10) to the activated Fas(CD95) or TNFR-1 receptors . The resulting aggregate, called the death-inducing signaling complex (DISC), carries out proteolytic activation of the enzyme caspase-8. Activated caspase-8 initiates the subsequent cascade of caspases that mediate apoptosis. Furthermore, the FADD protein is involved in the interferon-mediated antiviral immune response and plays a role in the positive regulation of interferon signaling.

Diseases associated with FADD include:

• Immunodeficiency 90 with encephalopathy functional hyposplenia and hepatic dysfunction.
• Otodental dysplasia (OMIM: 166750).

Misregulation of the caspase cascade can lead to severe diseases. One example is Huntington's disease, in which an initiator caspase is activated at the wrong time, causing healthy cells to die. Blocking the caspase with drugs can suppress this process.

1. Bolze A et al (2010) Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet 87: 873-881.
2. Kohn LA et al (2020) Novel compound heterozygote variations in FADD identified to cause FAS-associated protein with death domain deficiency. J Clin Immun 40: 658-661.
3. Marín-Rubio JL et al (2019) FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications. Cancers (Basel) 11:1462.
4. Savic S et al (2015) A new case of Fas-associated death domain protein deficiency and update on treatment outcomes. J Allergy Clin Immun 136: 502-505.