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Am J Hum Genet. Dec 10, 2010; 87(6): 873–881.
PMCID: PMC2997374

Whole-Exome-Sequencing-Based Discovery of Human FADD Deficiency

Abstract

Germline mutations in FASL and FAS impair Fas-dependent apoptosis and cause recessively or dominantly inherited autoimmune lymphoproliferative syndrome (ALPS). Patients with ALPS typically present with no other clinical phenotype. We investigated a large, consanguineous, multiplex kindred in which biological features of ALPS were found in the context of severe bacterial and viral disease, recurrent hepatopathy and encephalopathy, and cardiac malformations. By a combination of genome-wide linkage and whole-exome sequencing, we identified a homozygous missense mutation in FADD, encoding the Fas-associated death domain protein (FADD), in the patients. This FADD mutation decreases steady-state protein levels and impairs Fas-dependent apoptosis in vitro, accounting for biological ALPS phenotypes in vivo. It also impairs Fas-independent signaling pathways. The observed bacterial infections result partly from functional hyposplenism, and viral infections result from impaired interferon immunity. We describe here a complex clinical disorder, its genetic basis, and some of the key mechanisms underlying its pathogenesis. Our findings highlight the key role of FADD in Fas-dependent and Fas–independent signaling pathways in humans.

Main Text

Germline mutations in FASL1 (MIM 134638) and FAS2,3 (MIM 134637) are genetic etiologies of autoimmune lymphoproliferative syndrome (ALPS [MIM 601859]) in humans. ALPS typically begins in early childhood (median age at onset: 2 yrs), with lymphadenopathy and/or splenomegaly. About half the patients have autoimmune disease, autoimmune cytopenias being particularly common.4,5 The patients do not suffer from unusually severe infection, unless they are on immunosuppressive treatment,4 and display no overt developmental phenotype. We investigated the molecular basis of a condition affecting at least four members of an extended consanguineous kindred of Pakistani origin (Figure 1A) with biological features of ALPS (high-circulating CD4CD8TCRαβ+ T-cell [DNT] counts, and elevated IL-10 and FasL serum levels), no clinical features of ALPS, a complex infectious phenotype with both viral and bacterial infections, and congenital cardiovascular malformations (Table 1 and Table S1 available online). This study was approved by the local institutional review board. Written informed consent for participation in the study was obtained from all patients and family members studied.

Figure 1
Characterization of an Inherited FADD Mutation
Table 1
Clinical Features of Four Patients in the Family

The affected children suffered from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction (modestly elevated transaminases without cholestasis, metabolic derangement, or synthetic defects), sometimes accompanied by generalized seizures that were difficult to control. Episodes lasted several days, sometimes requiring intensive care, and cranial imaging in three patients (P1, P3, and P4 [IV.2, IV.4, and IV.5 in Figure 1]) suggested atrophy, despite subsequent recovery in two of these patients (P1 and P3). For some of the episodes, it was possible to identify a viral trigger: varicella zoster virus (VZV), measles mumps rubella (MMR) attenuated vaccine, parainfluenza virus, and Epstein-Barr virus (EBV). The index case, P3 (IV.4 in Figure 1), died at the age of 4 yrs, during such an episode. In addition, fatal invasive pneumococcal disease occurred in two children (P1 and P2 [IV.2 and IV.3 in Figure 1]), and Howell-Jolly bodies were detected in the two remaining patients (P3 and P4 [IV.4 and IV.5 in Figure 1]), despite the presence of a spleen (indicating functional hyposplenism).6–8 This clinical syndrome has never before been described (no MIM number). In the previous generation, another five family members had died in childhood, two with “epilepsy” and two from infection (pneumonia and measles, respectively) (data not shown), suggesting that there may have been up to nine patients with this disorder in these two generations of this kindred.

We hypothesized that this syndrome would segregate as an autosomal-recessive trait. We investigated its genetic etiology, by combining genome-wide linkage analysis by homozygosity mapping with whole-exome sequencing.9–11 For the linkage analysis, we genotyped three affected patients (P2, P3, and P4), their parents (III.1, III.2, III.3, and III.4), and one healthy sibling (IV.1) with the Affymetrix 500K SNP Array or the Affymetrix 6.0 Array. No material was available for P1. Homozygous regions were detected with the HomozygosityMapper genome browser. Two regions (> 1 Mb) were homozygous in the three affected patients and heterozygous in other members of the family: an 8 Mb region on chromosome 11 (between rs4930243 and rs7926553; bp position: g.68,499,874– g.76,470,079; hg18, NCBI 36.1) and a 9 Mb region on chromosome 18 (between rs9959449 and rs12327522; bp position: g.60,703,632–g.70,387,399; hg18, NCBI 36.1). The regions were further confirmed by typing microsatellite markers (Figure S1).

In parallel to the linkage analysis, we sequenced the exome of P3 with the SureSelect Human All Exon Kit (Agilent Technologies). The sequences obtained were aligned to the reference genome (hg18 build) with the Burrows-Wheeler Aligner. Three open-source packages were used for downstream processing and variant calling: the Genome Analysis Toolkit (GATK),12 SAMtools,13 and Picard Tools. Substitution calls were made with the GATK UnifiedGenotyper. All calls with a read coverage < 4× and a phred-scaled SNP quality of < 30 were filtered out. All the variants were annotated with SeattleSeq SNP Annotation. In total, we identified 23,146 variations. Of these, 67 variants were found in the chromosome 11 candidate region, and 14 variants were found in the chromosome 18 candidate region (Table S2). Comparisons with the NCBI dbSNP build 129, the 1000 Genomes Project database, and our in-house database (composed of 70 exomes) identified only one nonsynonymous variant that had not been reported before and mapped to the chromosome 11 region. No previously unreported nonsynonymous variant mapping to the linked region on chromosome 18 was identified. The variant identified was a missense homozygous c.315T>G in exon 2 of FADD (NM_003824.3, MIM 602457) that changes cysteine at amino acid position 105 to tryptophan, p.C105W (referred to as C105W hereafter) (Figure 1B and Figure S2). Cysteine at amino acid position 105 is highly conserved throughout evolution (Figure 1C). We validated this variant by Sanger sequencing on genomic DNA from peripheral blood and on cDNA from EBV-transformed B cells (EBV-B). This variant segregated with the disease status in all family members examined (Figure 1A) and was not found in 282 Pakistani controls, suggesting that it is not an irrelevant polymorphism.

FADD was first described as an adaptor protein interacting with the apoptosis-inducing surface receptor Fas.14 It has since been shown to interact with various partners and to participate in many other cellular processes, such as autophagy, inflammation, innate immunity, cell proliferation, and tumor development.15–18 Thus, we hypothesized that the FADD mutation was responsible for the complex clinical phenotype of the affected individuals. To test this hypothesis, we assessed the expression of FADD mRNA levels in EBV-B cells by quantitative RT-PCR. We found that FADD mRNA levels in the EBV-B cells from P3 (C105W/C105W) were similar to those in the EBV-B cells from IV.1 (WT/WT) (data not shown). However, FADD protein levels were clearly lower in primary fibroblasts from P4 (~16%) than in primary fibroblasts from a healthy control (Figures 1D and 1E). Similarly, FADD protein levels were lower in the EBV-B cells from P3 (~21%) and III.1 (WT/C105W) (~62%) than in the EBV-B cells from IV.1 (Figures 1D and 1F). Residue C105 is located in alpha-helix 1 of the FADD death domain (DD), at the interface of the Fas-FADD complex.19 We tested the effect of the C105W mutation on FADD folding stability and Fas-FADD interaction with recombinant Fas DD and FADD DD proteins. The C105W mutant protein was folded, as shown by differential scanning calorimetry (DSC), but the folding stability of the mutant protein was lower than that of WT FADD, by ~10°C (Figure 1G). We then assessed the effect of the mutation on Fas-FADD complex stability by using a gel copurification assay in the presence of increasing concentrations of NaCl (Figure 1H). Binding levels for C105W FADD and Fas were clearly lower than those for WT FADD, suggesting that the primary Fas-FADD complex was less stable. Thus, the C105W mutation in FADD strongly decreases steady-state protein levels and impairs the interaction of the residual FADD protein with Fas.

FADD forms a critical bridge between the death receptor Fas and caspase-8 (MIM 601763), in a multimolecular array known as the death-inducing signaling complex (DISC).20,21 We therefore studied Fas-induced apoptosis in the patients' cells. Phytohemagglutinin-stimulated peripheral-blood lymphocytes (PHA blasts) from P4 displayed impaired apoptosis (viability >50% higher than for controls) when challenged with cross-linked Fas ligand (FasL), similar to Fas-deficient cells (Figure 2A). In addition, EBV-B cells from P3 displayed impaired apoptosis when Fas was crosslinked with agonistic Fas-specific antibody (Apo1.3) (Figure 2B). In keeping with this finding, investigations of the surviving patient P4 revealed several features classically associated with ALPS due to Fas2,3 or FasL1 deficiency and more rarely associated with deficiencies of caspase-8 or caspase-10 (MIM 601762).4,22,23 P4 displayed an expansion of the population of mature CD4CD8TCRαβ+ T cells (DNT) in peripheral blood, as well as elevated serum levels of IL-10 and soluble FasL (Table 1 and Figures 2C and 2D).24,25 Our data confirm that the FADD C105W variant impairs apoptotic function both in vitro and in vivo, resulting in biological features of ALPS despite the lack of clinically evident autoimmunity or lymphoproliferation (although P4 did have transiently detectable antierythrocyte autoantibodies and P2, P3, and P4 displayed peripheral lymphocytosis [Table S1]). T cell proliferation in response to various stimuli was normal (Figure 2E), in contrast with findings for caspase-8 deficient individuals22 and mice with FADD deficiency specific to T or B cells.26 A recent study in mice suggested that FADD deficiency may decrease T cell proliferation as a result of an excess of necroptosis.16 To examine whether C105W affected necroptosis, we added an inhibitor of necroptosis, necrostatin 1, to CD3- and CD28-stimulated proliferation assays. Necrostatin-1 did not affect proliferative responses in this system (Figure S3).

Figure 2
Characterization of the ALPS Phenotype

The laboratory findings for the FADD-deficient patients were typical of ALPS, but clinical presentation was dominated by features absent from classical ALPS, leading to early death. These features included invasive pneumococcal disease (IPD), which killed both P1 and P2. Neither P3 nor P4 suffered from IPD, probably because they were on antibacterial prophylaxis from early infancy, but abnormally high counts of Howell-Jolly bodies were seen on their blood smears. The identification of Howell-Jolly bodies on peripheral-blood smears is the most reliable indicator of impaired splenic phagocyte function (including functional or anatomical asplenia).6–8 Moreover, asplenia (MIM 271400 and MIM 208530)—whether anatomical or functional, congenital or acquired—has frequently been associated with a strong predisposition to infections by encapsulated bacteria, such as IPD, in particular.6–8,27 For example, we showed that 15 of 20 patients with isolated congenital asplenia (ICA) suffered from invasive bacterial infections, caused mostly by Streptococcus pneumoniae (61%).27 Finally, B cell responses to vaccine antigens appeared to be intact in the patients (Table S1), ruling out other known causes of IPD.28 These observations suggest that functional hyposplenism underlies IPD in FADD-deficient patients.

In addition to IPD, FADD-deficient patients suffered from recurrent episodes of encephalopathy and liver dysfunction with fever, which were sometimes triggered by viral infection (Table 1). Previous studies in mouse embryonic fibroblasts (MEFs) suggested that FADD plays a crucial role in type I interferon (IFN) -dependent antiviral immunity.15,29 We therefore tested the hypothesis that the unusually severe illnesses associated with viral infections in FADD-deficient patients might be due to an impaired type I IFN-dependent antiviral response, by assessing the antiviral effect of IFN-α in vesicular stomatitis virus (VSV)-infected P3 and IV.1 EBV-B cells. STAT1-deficient EBV-B cells, lacking a key type-I-IFN-responsive pathway,29–31 were included as controls. Prior treatment with IFN-α protected both P3 and IV.1 cells from VSV-induced cell death until 36 hr after infection (Figure 3A). However, IFN-α-treated P3 cells eventually succumbed to VSV infection, whereas IFN-α-treated IV.1 cells remained protected until 60 hr after infection (Figures 3A and 3B). These results suggest that the IFN-α-responsive pathway is intact but that the positive feedback of IFN signaling is impaired in FADD-deficient cells. Interferon regulatory factor 7 (IRF7), induced by autocrine type I IFNs, is known to play a critical role in the positive feedback of IFN signaling, by inducing IFN-α gene family members. We found that the induction of IRF7 in response to VSV infection was impaired in P3 cells, despite levels of IFN-β induction similar to those in IV.1 cells (Figure 3C). These data provide a molecular basis for the increase in susceptibility to viral diseases in FADD-deficient patients.

Figure 3
Impaired Antiviral Immunity

By contrast, we can only speculate about the mechanisms underlying the developmental abnormalities within this kindred. P3 displayed pulmonary atresia (MIM 178370) and P4 had a left-sided superior vena cava (SVC) draining into the left atrium, both of which are rare as sporadic defects and were probably caused by FADD insufficiency. Indeed, mice with a null mutation in FADD are not viable because of embryonic defects, including cardiac abnormalities, such as thinning of the ventricular myocardium.32 Moreover, FADD expression in mice, at embryonic day 11.5, is detected not only in the myocardium but also in the brain, liver, and developing vertebrae.32 Spinal anatomy appeared normal in all FADD-deficient patients, but hepatic and cerebral dysfunctions were clearly key elements of the disease phenotype. Cerebral atrophy was observed in P1, P3, and P4 at a very early age and appeared to be progressive in P4 (scan images in Figure S4), despite continuing neurodevelopment (Table 1). This, and the mild portal fibrosis observed on liver biopsy in two patients (Figures 4J–4L), should be considered as sequelae of FADD deficiency. Finally, FADD seems to be important for the development of a functional spleen in humans, as demonstrated by the presence of Howell-Jolly bodies—the hallmark of a lack of splenic function—in the blood smears of P3 and P4.7,8 In P2, a limited postmortem examination of lymph nodes, spleen, and thymus revealed no histological features of ALPS or other lymphoid tissue abnormalities (Figure 4). However, the spleen showed an expanded, congested red pulp containing increased neutrophils, consistent with sepsis. Moreover, the normal cord-sinus architecture of the red pulp was not readily apparent; reticulin deposition appeared disordered, normal sinusoidal “barrel hoop” fibers were not identified, and macrophages appeared haphazardly arranged (Figures 4C–4I). Examination of spleen histology in other affected individuals is unlikely to be possible, thus precluding firm conclusions regarding the relationship between human FADD deficiency and disordered red pulp microarchitecture. The prominence but incomplete penetrance of cardiac, cerebral, hepatic, and splenic abnormalities in the clinical phenotype strongly suggests the existence of organ-specific effects of FADD deficiency worthy of further study in suitably designed mouse models.

Figure 4
Histopathology of P2 and P4

In conclusion, we have described the clinical features of an autosomal-recessive inherited disorder with biological features of ALPS, susceptibility to bacterial and viral infections, and developmental abnormalities. Furthermore, we have determined its genetic etiology, which results in FADD deficiency in the affected children, by genome-wide linkage analysis and whole-exome sequencing. Finally, we have dissected the molecular mechanisms of disease for several aspects of this phenotype, including bacterial susceptibility (functional hyposplenism), viral susceptibility (impaired IFN immunity), and features of ALPS (impaired Fas-dependent apoptosis). Other phenotypes, particularly those of a developmental nature, remain unexplained but are probably due to the disruption of Fas-independent pathways, given that they were not documented in Fas-deficient patients. These unanticipated findings highlight the power of exome sequencing used in combination with genome-wide linkage analysis within consanguineous families.9–11,33 We anticipate rapid advances in molecular medicine,5,9 facilitated by this strategy, in the coming years.

Acknowledgments

We thank the patients' family for their trust and all members of our laboratories for helpful discussions. We thank Capucine Picard for her expert analysis of the lymphocyte subsets of the patients. We thank Louise Tee for technical assistance and SNP genotyping and Shanaz Pasha for patient ascertainment. We thank Magorzata Dobaczewska for the production of proteins in bacteria and Andrey Bobkov (protein facility at SBMRI) for DSC measurement. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from INSERM, University Paris Descartes, The Rockefeller University Center for Clinical Translational Science (grant number 5UL1RR024143-03), The Rockefeller University, and St. Giles Foundation. The laboratory of S.H. is supported by an MRC grant (G0701897). This work was also supported by a R01AA017238 grant to S.J.R., by an ANR grant (ANR-08-GENO-015-01) to F.R.L., and by the WellChild foundation. M.B. is supported by a fellowship from the Cancer Research Institute.

Supplemental Data

Document S1. Four Figures and Two Tables:

Web Resources

The URLs for the data presented here are as follows:

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