Alternative titles; symbols
HGNC Approved Gene Symbol: FADD
Cytogenetic location: 11q13.3 Genomic coordinates (GRCh38): 11:70,203,296-70,207,390 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.3 | Immunodeficiency 90 with encephalopathy, functional hyposplenia, and hepatic dysfunction | 613759 | Autosomal recessive | 3 |
FADD is a universal adaptor protein in apoptosis that mediates signaling of all known death domain-containing members of the TNF receptor superfamily (Kabra et al., 2001).
Two cell surface cytokine receptors, FAS (134637) and the tumor necrosis factor (TNF) receptor (see TNFR1, 191190), trigger apoptosis by natural ligands or specific agonist antibodies. Both receptors contain a conserved intracellular death domain. Using a yeast 2-hybrid screen with the cytoplasmic domain of FAS as bait, Chinnaiyan et al. (1995) isolated FADD (FAS-associating protein with death domain) cDNAs. The predicted 208-amino acid protein contained a death domain that was 25 to 30% identical to those of FAS and TNFR1. FADD interacted with FAS both in vitro and in vivo.
Kim et al. (1996) reported that the FADD gene contains 2 exons and spans approximately 3.6 kb.
By analysis of somatic cell hybrid panels and by fluorescence in situ hybridization, Kim et al. (1996) mapped the FADD gene to 11q13.3. They noted that this region is amplified in several human malignancies (see EMS1; 164765), and found that FADD, along with other genes on 11q13.3, was amplified in a breast cancer cell line.
Crystal Structure
Scott et al. (2009) successfully formed and isolated the human FAS (134637)-FADD death domain complex and reported the 2.7-angstrom crystal structure. The complex shows a tetrameric arrangement of 4 FADD death domains bound to 4 FAS death domains. Scott et al. (2009) showed that an opening of the FAS death domain exposes the FADD binding site and simultaneously generates a FAS-FAS bridge. The result is a regulatory FAS-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental death-induced signaling complex (DISC) assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. Scott et al. (2009) concluded that, in addition to depicting a previously unknown mode of death domain interactions, their results further uncover a mechanism for receptor signaling solely by oligomerization and clustering events.
Chinnaiyan et al. (1995) demonstrated that the in vivo interaction of FADD with FAS was due to the association of the respective death domains. Overexpression of FADD in mammalian cells induced apoptosis, which like FAS-induced apoptosis, was blocked by CrmA, a poxvirus gene product. Northern blot analysis revealed that FADD is expressed as a 1.6-kb mRNA in many fetal and adult tissues. The authors concluded that FADD may play an important role in the proximal signal transduction of FAS. Yeh et al. (1998) stated that the interaction of FADD and FAS through their C-terminal death domains unmasks the N-terminal effector domain of FADD, allowing it to recruit caspase-8 (CASP8; 601763) to the FAS signaling complex and thereby activating a cysteine protease cascade, leading to cell death.
Balachandran et al. (2004) reported that mammalian cells lacking the death domain-containing protein FADD are defective in intracellular double-stranded RNA (dsRNA)-activated gene expression, including production of type I (alpha/beta) interferons (e.g., 147660), and are thus very susceptible to viral infection. The signaling pathway incorporating FADD is largely independent of Toll-like receptor-3 (TLR3; 603029) and the dsRNA-dependent kinase PKR (176871) but seems to require receptor-interacting protein-1 (RIPK1; 603453) as well as TANK-binding kinase-1 (604834)-mediated activation of the transcription factor IRF3 (603734). The requirement for FADD in mammalian host defense is evocative of innate immune signaling in Drosophila, in which a FADD-dependent pathway responds to bacterial infection by activating the transcription of antimicrobial genes. Balachandran et al. (2004) concluded that their data further suggest the existence of a conserved pathogen recognition pathway in mammalian cells that is essential for the optimal induction of type I interferons and other major genes important for host defense.
Lee et al. (2007) showed that intrinsic apoptosis in human cells that was induced by the chemotherapeutic agent etoposide or the antibiotic staurosporine, but not by FAS ligand (TNFSF6; 134638) or TRAIL (TNFSF10; 603598), caused translocation of AK2 (103020) from mitochondria to the cytoplasm, followed by formation of a complex between AK2, FADD, and CASP10 (601762). Yeast 2-hybrid analysis, protein pull-down assays, and immunoprecipitation analysis showed that the N- and C-terminal domains of AK2, which include nucleoside- and substrate-binding domains, respectively, bound the C-terminal death domain of FADD. AK2 binding promoted association of CASP10 with FADD, and addition of purified AK2 protein to cell extracts induced activation of CASP10 via FADD, leading to subsequent activation of CASP9 (602234) and CASP3 (600636). Apoptosis through the AK2 complex did not correlate with the adenylate kinase activity of AK2, did not require CASP8-mediated apoptotic responses, and did not involve mitochondrial cytochrome c release. Immunodepletion or knockdown of AK2, FADD, or CASP10 abrogated etoposide-induced apoptosis, and AK2 complexes were not observed in several etoposide-resistant human tumor cell lines that were deficient in expression of FADD, CASP10, or CASP3. In contrast to the findings in human cells, etoposide-induced apoptosis was observed in mouse embryonic fibroblasts that lacked Fadd expression. Since mice also lack Casp10, Lee et al. (2007) concluded that mice lack an apoptotic pathway comparable to the AK2-FADD-CASP10 pathway in humans.
By stimulating human microvascular endothelial cells expressing FADD with lipopolysaccharide (LPS), which activates the TLR4 (603030) signaling pathway, Zhande et al. (2007) showed that FADD attenuated JNK (MAPK8; 601158) and PI3K (see 171834) pathway activation in a death domain-dependent manner. Mouse cells lacking Fadd showed hyperactivation of these pathways. Coimmunoprecipitation and immunoblot analyses in human cells revealed that FADD interacted with IRAK1 (300283) and MYD88 (602170). LPS stimulation increased IRAK1-FADD interaction and recruitment of the complex to activated MYD88. In mouse cells lacking Irak1, Fadd did not associate with Myd88. IRAK1-mediated shuttling of FADD to MYD88 allowed for controlled and limited activation of the TLR4 signaling pathway. Enforced FADD expression inhibited LPS-induced, but not VEGF (VEGFA; 192240)-induced, endothelial cell sprouting. Fadd deficiency in mouse cells led to enhanced proinflammatory cytokine production induced by stimulation of Tlr4 and Tlr2 (603028), but not Tlr3, and reconstitution of Fadd reversed the enhanced proinflammatory cytokine production. Zhande et al. (2007) concluded that FADD is a negative regulator of IRAK1/MYD88-dependent responses in innate immune signaling.
Li et al. (2013) discovered that death domains in several proteins, including TRADD (603500), FADD, RIPK1, and TNFR1 (191190), were directly inactivated by NleB, an enteropathogenic E. coli type III secretion system effector known to inhibit host NF-kappa-B (see 164011) signaling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (arg235 in the TRADD death domain). NleB GlcNAcylation of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signaling in enteropathogenic E. coli infected cells, including NF-kappa-B signaling, apoptosis, and necroptosis. Type III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of a FADD-mediated death-inducing signaling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of enteropathogenic E. coli infection.
Pearson et al. (2013) reported that the type III secretion system (T3SS) effector NleB1 from enteropathogenic E. coli binds to host cell death-domain-containing proteins and thereby inhibits death receptor signaling. Protein interaction studies identified FADD, TRADD, and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical DISC and proteolytic activation of caspase-8 (601763), an essential step in death receptor-induced apoptosis. This inhibition depended on the N-acetylglucosamine transferase activity of NleB1, which specifically modified arg117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defense was demonstrated using mice deficient in the FAS signaling pathway, which showed delayed clearance of the enteropathogenic E. coli-like mouse pathogen Citrobacter rodentium and reversion to virulence of an NleB mutant. Pearson et al. (2013) concluded that the activity of NleB suggested that enteropathogenic E. coli and other attaching and effacing pathogens antagonize death receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.
Otodental Dysplasia
In 2 families with otodental dysplasia (166750) and 1 with otodental dysplasia and coloboma, Gregory-Evans et al. (2007) identified overlapping hemizygous microdeletions on chromosome 11q13, the smallest of which spanned 43 kb and involved the FGF3 gene (164950). In the family with otodental dysplasia and coloboma, the microdeletion was spanned 490 kb and encompassed the FADD gene. Spatiotemporal in situ hybridization in zebrafish embryos showed that FADD is expressed during eye development. Gregory-Evans et al. (2007) suggested that FGF3 haploinsufficiency is likely the cause of otodental syndrome and that FADD haploinsufficiency accounts for the associated ocular coloboma.
Immunodeficiency 90 With Encephalopathy, Functional Hyposplenia, And Hepatic Dysfunction
In 2 sisters and their cousin from a large consanguineous Pakistani pedigree who had immunodeficiency-90 with encephalopathy, functional hyposplenia, and hepatic dysfunction (IMD90; 613759), Bolze et al. (2010) identified homozygosity for a missense mutation in the FADD gene (C105W; 602457.0001).
In a Pakistani girl, born of consanguineous parents, with IMD90, Savic et al. (2015) identified a homozygous C105W mutation in the FADD gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Savic et al. (2015) did not perform functional studies of the mutation, but noted that it had been shown to impair FADD interaction with FAS (CD95; 134637), resulting in defective FAS-mediated cell apoptosis in vitro (Bolze et al., 2010).
In a boy, born of unrelated parents, with IMD90, Kohn et al. (2020) identified compound heterozygous mutations in the FADD gene (602457.0002 and 602457.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells had decreased FADD protein levels compared to controls. Functional studies of the variants were not performed.
Yeh et al. (1998) found that FAS (CD95), TNFR1, and death receptor 3 (603366) did not induce apoptosis in FADD-deficient embryonic fibroblasts, whereas DR4, oncogenes E1A and c-myc (190080), and chemotherapeutic agent adriamycin did. Mice with a deletion in the FADD gene did not survive beyond day 11.5 of embryogenesis; these mice showed signs of cardiac failure and abdominal hemorrhage. Chimeric embryos showing a high contribution of FADD-null mutant cells to the heart reproduced the phenotype of FADD-deficient mutants. Thus, not only death receptors but also receptors that couple to developmental programs may use FADD for signaling. Since FAS is necessary for homeostasis in the immune system, Zhang et al. (1998) investigated the effect of FADD deletion in lymphoid organs. Since FADD-null mice die in utero, they used FADD-null, RAG1 (179615)-null chimeras in which all mature lymphocytes were derived from the FADD-null cells, as RAG1-null mice are not capable of producing B or T cells. FAS-induced apoptosis was completely blocked in thymocytes from the FADD-null mice, indicating that there are no redundant FAS apoptotic pathways. Although thymocyte subpopulations were apparently normal in newborn chimeras, the thymocytes decreased to undetectable levels as these mice age. Peripheral T cells were present in all older FADD-null chimeras, but activation-induced proliferation was impaired despite production of IL2 (147680). These results and the similarities between FADD-null mice and mice lacking the beta-subunits of the IL2 receptor (IL2RB; 146710), suggested to Zhang et al. (1998) that there is an unexpected connection between cell proliferation and apoptosis.
FADD-null mutations in mice are embryonic-lethal, and analysis of FADD -/- T cells from RAG-1 -/- reconstituted chimeras suggested a role for FADD in proliferation of mature T cells. Kabra et al. (2001) reported the generation of T cell-specific FADD-deficient mice via a conditional genomic rescue approach. They found that FADD deficiency led to inhibition of T cell development at the CD4(-)/CD8(-) stage and a reduction in the number of mature T cells. The FADD mutation did not affect apoptosis or the proximal signaling events of the pre-T-cell receptor; introduction of a T-cell receptor transgene failed to rescue the mutant phenotype. These data suggested that FADD, through either a death domain-containing receptor or a novel receptor-independent mechanism, is required for the proliferative phase of early T cell development.
Zhang et al. (2011) showed that FADD-null embryos contain raised levels of RIP1 (603453) and exhibit massive necrosis. To investigate a potential in vivo functional interaction between RIP1 and FADD, null alleles of RIP1 were crossed into Fadd-null mice. Notably, RIP1 deficiency allowed normal embryogenesis of Fadd-null mice. Conversely, the developmental defect of Rip1-null lymphocytes was partially corrected by FADD deletion. Furthermore, RIP1 deficiency fully restored normal proliferation in Fadd-null T cells but not in Fadd-null B cells. Fadd-null/Rip1-null double-knockout T cells are resistant to death induced by Fas or TNF-alpha (191160) and show reduced NF-kappa-B (see 164011) activity. Therefore, Zhang et al. (2011) concluded that their data demonstrated an unexpected cell type-specific interplay between FADD and RIP1, which is critical for the regulation of apoptosis and necrosis during embryogenesis and lymphocyte function.
Welz et al. (2011) showed that mice with intestinal epithelial cell (IEC)-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis, and severe erosive colitis. Genetic deficiency in RIP3 (605817), a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD (605018), a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) (300248) mice, showing that different mechanisms mediated death of colonic epithelial cells in these 2 models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like receptor signaling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF, or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defense, maintains homeostasis, and prevents chronic intestinal inflammation. Welz et al. (2011) concluded that, collectively, their results showed that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicated that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.
In 2 sisters and their cousin from a large consanguineous Pakistani pedigree with immunodeficiency-90 with encephalopathy, functional hyposplenia, and hepatic dysfunction (IMD90; 613759), Bolze et al. (2010) identified homozygosity for a c.315T-G (c.315T-G, NM_003824) transversion in exon 2 of the FADD gene, resulting in a cys105-to-trp (C105W) substitution at a highly conserved residue in alpha-helix-1 of the FADD death domain (DD), at the interface of the FAS (134637)-FADD complex. The mutation segregated with disease in the family and was not found in 282 Pakistani controls. Analysis of patient EBV-B cells showed levels of FADD mRNA that were similar to controls; however, FADD protein levels were clearly lower in patient fibroblasts (16% and 21%) and a heterozygous relative (62%) compared to controls. Differential scanning calorimetry showed that the folding stability of the mutant protein was lower than that of wildtype by 10 degrees C, and gel copurification assay showed that binding levels for C105W-mutant FADD with FAS were lower than those for wildtype FADD, suggesting that the primary FAS-FADD complex was less stable. Bolze et al. (2010) concluded that the C105W mutation strongly decreases steady-state protein levels and impairs the interaction of the residual FADD protein with FAS. Analysis of FAS-induced apoptosis in patients' cells confirmed that the C105W mutant impairs apoptotic function both in vitro and in vivo.
In a Pakistani girl, born of consanguineous parents, with IMD90, Savic et al. (2015) identified a homozygous C105W mutation in the FADD gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Savic et al. (2015) did not perform functional studies of the mutation, but noted that it had been shown to impair FADD interaction with FAS (CD95; 134637), resulting in defective FAS-mediated cell apoptosis in vitro (Bolze et al., 2010).
In a boy, born of unrelated parents, with immunodeficiency-90 with encephalopathy, functional hyposplenia, and hepatic dysfunction (IMD90; 613759), Kohn et al. (2020) identified compound heterozygous mutations in the FADD gene: a c.313T-C transition, resulting in a cys105-to-arg (C105R) substitution at a highly conserved residue in the death domain, and a 7-bp deletion (c.52_58delGACGAGC; 602457.0003), predicted to result in a frameshift and premature termination. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The C105R variant was found at a low frequency only in the heterozygous state in gnomAD (less than 0.001%), whereas the frameshift mutation was not found in gnomAD. Patient T cells had decreased FADD protein levels compared to controls. Functional studies of the variants were not performed.
For discussion of the 7-bp deletion (c.52_58delGACGAGC) in the FADD gene, predicted to result in a frameshift and premature termination, that was found in compound heterozygous state in a patient with immunodeficiency-90 with encephalopathy, functional hyposplenia, and hepatic dysfunction (IMD90; 613759) by Kohn et al. (2020), see 602457.0002.
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