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Resume Introduction Le syndrome de Griscelli (SG) est une maladie genetique autosomique recessive rare, caracterisee par une dilution pigmentaire des cheveux et de la peau. Nous rapportons un cas de syndrome de Griscelli de type 3 diagnostique a un âge tardif. Observation Une femme de 31 ans presentait depuis l’enfance une depigmentation des cheveux et des sourcils avec une discrete leucodermie diffuse. L’etude microscopique du cheveu mettait en evidence des agregats de melanine irregulierement distribues le long de la tige pilaire. Le sequencage de l’ADN montrait une mutation homozygote C103T (R35W) dans l’exon 1 du gene MLPH, correspondant au syndrome de Griscelli type 3. Discussion Trois phenotypes cliniques de SG ont ete decrits selon le defaut moleculaire sous-jacent. Les SG types 1 et 2 sont associes respectivement a un dysfonctionnement du systeme nerveux central et a un deficit immunitaire. Le SG type 3 est une forme cutanee isolee. L’examen microscopique des cheveux permet de poser le diagnostic. Seuls 15 cas de SG type 3 ont ete decrits dans la litterature, neuf de sexe masculin et six de sexe feminin. L’âge moyen au diagnostic est de 12 ans. Dix des cas sont d’origine arabe, quatre d’origine turque et un d’origine indienne. La mutation R35W a ete observee dans neuf cas et les mutations E98X et R35Q chacune dans un cas. Conclusion Le syndrome de Griscelli doit etre evoque devant tout aspect de cheveux gris argentes, plus particulierement chez des patients d’origine arabe ou turque.

Genetic skin diseases encompass a vast, complex, and ever expanding field. Recognition of the features of these diseases is important to ascertain a correct diagnosis, initiate treatment, consider genetic counseling, and refer patients to specialists when the disease may impact other areas. Because genodermatoses may present with a vast array of features, it can be bewildering to memorize them. This manuscript will explain and depict some genetic skin diseases that occur in both humans and domestic animals and offer a connection and memorization aid for physicians. In addition, we will explore how animal diseases serve as a model to uncover the mechanisms of human disease. The genetic skin diseases we will review are pigmentary mosaicism, piebaldism, albinism, Griscelli syndrome, ectodermal dysplasias, Waardenburg syndrome, and mucinosis in both humans and domesticated animals.

Resumen: Introducción: El síndrome hemofagocítico (SH) constituye una manifestación común a una serie de anomalías congénitas que afectan a la excreción lisosomal, interrumpiendo la vía citolítica gránulodependiente y desencadenando una disfunción de la sinapsis inmunológica. La presencia de manifestaciones características en otros tejidos puede orientar el diagnóstico etiológico. Pacientes y métodos: Presentamos los hallazgos clínicos y biológicos de dos hermanos diagnosticados de linfohistiocitosis hemofagocítica familiar tipo 3 (FHL-3), dos pacientes con síndrome de Griscelli tipo 2 (GS-2), y un síndrome de Chédiak-Higashi (CHS). Resultados: Los pacientes de FHL-3 aportaron un resultado positivo en el estudio mutacional de UNC13D indicado por un SH precoz en el primero de ellos. El primer diagnóstico de SG-2 se confirmó por la presencia de una mutación en el gen Rab27A en una paciente con SH en la que había un llamativo trastorno de la pigmentación. La misma mutación se detectó en una prima afecta también de trastornos de la pigmentación. El diagnóstico de SCH se realizó en un paciente que presentaba un SH con trastornos de la pigmentación y granulación atípica en células hematopoyéticas. El hallazgo de una mutación en el gen LYST confirmó el diagnóstico. Conclusiones: En los pacientes con SH primario es preciso atender a manifestaciones extra-inmunológicas características de ciertos trastornos de la secreción lisosomal. La curiosa relación entre albinismo e inmunidad ha jugado recientemente un papel decisivo en la identificación de los mecanismos moleculares involucrados en estos procesos. Abstract: Introduction: Haemophagocytic syndrome (HS) is a common manifestation of several congenital disorders characterised by a disruption of lysosomal secretion, interrupting the cytolytic pathway and triggering a dysfunction in the immune synapse. In this situation, the recognition of certain extra-immunological manifestations may help in the diagnostic process. Patients and methods: We describe the clinical and biological features present in two brothers with familial haemophagocytic lymphohistiocytosis type 3 (FHL-3), two patients with Griscelli syndrome type 2 (GS-2) and one patient with Chédiak-Higashi syndrome (CHS). Results: Mutational assays at UNC13D were carried out on two brothers after diagnosing an early onset HS in the first one, yielding a positive result in both cases with a consequent diagnosis of FHL-3. The diagnosis of GS-2 was supported by positive results of mutational Rab27A studies in one patient with HS and abnormal pigmentation, and in her cousin who was affected by a similar abnormal pigmentation. The diagnosis of CHS was established in one patient with HS, abnormal pigmentation and atypical granules on cytological examination of a bone marrow smear. Diagnosis was confirmed in this patient by the finding of a homozygous LYST mutation. Conclusions: We point out the importance of recognising the presence of typical extra-immunological manifestations of certain congenital disorders of lysosome secretion in patients diagnosed with HS. The association of albinism and immunodeficiency has played a critical role in the recent identification of the molecular mechanism involved in these disorders.

Griscelli syndrome (GS), a rare autosomal recessive disorder characterized by partial albinism and immunological impairment and/or severe neurological impairment, results from mutations in the MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) genes. We identified a Hispanic patient born of a consanguineous union who presented with immunodeficiency, partial albinism, hepatic dysfunction, hemophagocytosis, neurological impairment, nystagmus, and silvery hair indicative of Griscelli syndrome type 2 (GS2). We screened for point mutations, but only exons 2–6 of the patient’s DNA could be PCR-amplified. Whole genome analysis using the Illumina® 1M-Duo DNA Analysis BeadChip identified a homozygous deletion in the patient’s DNA. The exact breakpoints of the 47.5-kb deletion were identified as chr15q15-q21.1: g.53332432_53379990del (NCBI Build 37.1); the patient lacks the promoter and 5’UTR regions of RAB27A, thus confirming the diagnosis of GS2.

Clonal natural killer (NK) and T cell expansions induced by Epstein- Barr virus (EBV) and genetic alterations compromising NK cell killing are the most common causes of hemophagocytic lymphohistocytosis (HLH). Generally, HLH is induced by an immune dysfunction where hypercytokinemia develops into reactive hemophagocytosis. In this work we review the causes of HLH and describe a case of a monoclonal expansion of EBV-negative NK cells associated to HLH in a seventeen-month-old girl suffering of Griscelli syndrome type-2 with novel RAB27A mutation and showing partial albinism, persistent fever, hepatosplenomegaly, adenopaties and cytopenias. At diagnosis, no evidence of active viral infections, including EBV, was found. Expansion of NK cells (5300/μl in peripheral blood) CD2+CD7+CD8+CD16+CD56+CD94+CD158a/h+CD158b/j–Perforin+ Granzyme B+ was found. After treatment (HLH-2004 protocol: Cyclosporin, Etoposide and Dexamethasone), NK cell count fell to 850/μl and progressively increased to pre-therapy levels by week 28. X-chromosome inactivation assay demonstrated NK cell monoclonality. NK cells sustained a strong killing and secreted high amounts of IFN-γ. At diagnosis, serum levels of sIL-2R (36,8 ng/ml) and IFN-γ (400 pg/ml) were elevated. In conclusion, we describe a monoclonal expansion of EBV-negative NK cells highly secretory of IFN-γ as the most probable cause of HLH episode in a patient with Griscelli syndrome type-2. NK cell count recovered normal levels and phenotype after bone marrow transplantation from her HLA identical sister.

SummaryRab27A is required for actin-based melanosome transport in mammalian skin melanocytes through its interaction with a specific effector, Slac2-a/melanophilin. Mutations that disrupt the Rab27A/Slac2-a interaction cause human Griscelli syndrome. The other Rab27 isoform, Rab27B, also binds all of the known effectors of Rab27A. In this study, we determined the crystal structure of the constitutively active form of Rab27B complexed with GTP and the effector domain of Slac2-a. The Rab27B/Slac2-a complex exhibits several intermolecular hydrogen bonds that were not observed in the previously reported Rab3A/rabphilin complex. A Rab27A mutation that disrupts one of the specific hydrogen bonds with Slac2-a resulted in the dramatic reduction of Slac2-a binding activity. Furthermore, we generated a Rab3A mutant that acquires Slac2-a binding ability by transplanting four Rab27-specific residues into Rab3A. These findings provide the structural basis for the exclusive association of Slac2-a with the Rab27 subfamily, whereas rabphilin binds several subfamilies, including Rab3 and Rab27.

The movement of melanosomes, dense melanin-containing organelles, within human melanocytes is actin-dependent and mediated through the formation of a Rab27a-Slac2-a-myosin Va (MyoVa) protein complex. We previously showed that only the melanocyte-specific exon F isoforms of MyoVa are involved in melanosome transport to the dendrite extremities. Here, we investigate siRNA to downregulate the exon F-containing isoforms of MyoVa in primary human melanocytes. Efficient and specific knockdown of the MyoVa exon F isofoms were shown at both mRNA and protein levels. Further, a stable shRNA against the MyoVa exon F isoforms was prepared by using a lentiviral system to improve and confirm the silencing effect in hard-to-transfect melanocyte cells. Immunofluorescence microscopy shows that knockdown of the exon F isoforms results in blockade of intramelanocytic melanosome transport due to the inability to form the Rab27a-Slac2-a-MyoVa tripartite complex. Interestingly, the observed phenotypic effect (that is, perinuclear accumulation of melanosomes) is the same as that seen in melanocytes from patients with human Griscelli syndrome causing abnormal pigmentation. We conclude that our siRNA-based strategy provides a previously unreported tool to block the intracellular melanosome movement in primary human melanocytes and may become an innovative drug to treat hyperpigmentation.

Udgivelsesdato: 2008-Jun The autosomal recessive Griscelli syndrome type II (GSII) is caused by mutations in the RAB27A gene. Typical clinical features include immunological impairment, silver-gray scalp hair, eyelashes and eyebrows and hypomelanosis of the skin. Rabs help determine the specificity of membrane trafficking steps within cells. In melanocytes, the GTP-bound form of Rab27A associates with the membranes of mature fully-pigmented melanosomes through its geranylgeranyl group. Once attached, Rab27A recruits the downstream effector Melanophilin (Mlph) and the actin-dependent motor protein Myosin Va (MyoVa). The molecular Rab27A/Mlph/MyoVA tripartite complex, which links melanosomes to the peripheral actin network, is required to achieve melanosome transfer to surrounding keratinocytes in the epidermis. Here we report a novel homozygous missense mutation c.127G>A, p.G43S in exon 2 of the RAB27A gene of an Afghani GSII patient. Laser scanning confocal microscopy showed that the G43S mutation, which is located in the highly conserved switch I region of Rab27A, induces perinuclear localization of melanosomes in normal melanocytes, and fails to restore melanosomes to the actin-rich periphery in GSII melanocytes. Co-immunoprecipitation studies showed that Rab27A(G43S) fails to interact with its effector Melanophilin, indicating that the switch I region functions in the recruitment of Rab effector proteins.

Griscelli syndrome is a rare autosomal-recessive disorder characterised by partial albinism, immunodeficiency, organomegaly and accelerated phases. During accelerated phases, pancytopenia, haemophagocytosis, hypoproteinemeia occur which may be accompanied by neurological deterioration. Primary neurological presentation is rare and we report a case that presented with obstructive hydrocephalus and infiltrative lesions in the brain unaccompanied by other features of accelerated phase. Biopsy of these lesions demonstrated sinus histiocytosis. Electron microscopy of hair shaft and genetic studies established the diagnosis of Griscelli disease with RAB 27A mutation.

The movement of melanosomes from post-Golgi compartments to the periphery of melanocytes is known to be regulated by factors including myosin Va and at least one Rab protein, Rab27a. Mutations in the genes encoding either protein in the mouse result in a hypopigmented phenotype mimicking the human disease Griscelli syndrome. Rab27b and Rab27a share 72% identity and they belong to the same melanocyte/platelet subfamily of Rab proteins. Rab27a orchestrates the transport of melanosomes by recruitment of the actin motor, myosin Va, onto melanosomes. By contrast, the function of Rab27b has remained elusive. In this study, we found that Rab27b mRNA is present in melanocytes and demonstrated the intrinsic GTPase activity of Rab27b protein. We explored the function of Rab27b by overexpression of two dominant negative mutants as well as the wild-type Rab27b in melan-a melanocytes. Green-fluorescent-protein-tagged Rab27b colocalizes with the melanosome marker tyrosinase-related protein 1 and with myosin Va at the cell periphery, whereas Rab27b mutants do not decorate melanosomes, and melanosomes in these mutant transfected cells redistribute from cell periphery to the perinuclear region. Furthermore, transient overexpression of the dominant negative forms of Rab27b caused diminution in both numbers and length of dendrites of melan-a cells. Our results suggest that Rab27b may regulate the outward movement of melanosomes and the formation or maintenance of dendritic extensions in melanocytes.

Chediak-Higashi syndrome and Griscelli syndrome are immune disorders that are characterized by a severe and often fatal hemophagocytic syndrome (HPS). Progress has been made in the characterization and understanding of the molecular basis involved in these inherited disorders. Defects in the CHS1/LYST protein in Chediak-Higashi syndrome and in the RAB27A protein in Griscelli syndrome lead to impairment of intracellular trafficking and secretion of several lysosomal proteins, including melanin from melanocytes and lytic enzymes from cytotoxic cells. These secretory defects cause hypopigmentation and a HPS, symptoms that characterize these two disorders. A neurologic form of Griscelli syndrome is caused by a deficiency in the molecular motor protein myosin-Va. The molecular characterization of these two conditions has identified new effectors of the secretory pathway and highlighted the pathway's determinant role in the regulation of lymphocyte homeostasis.

Myosin Va is a member of the unconventional class V myosin family, and a mutation in themyosin Va gene causes pigment granule transport defects in human Griscelli syndrome and dilute mice. How myosin Va recognizes its cargo (i.e. melanosomes), however, has re- mained undetermined over the past decade. In this study, we discovered Slac2-a/melanophilin to be the “missing link” between myosin Va and GTP-Rab27A present in the melanosome. Deletion analysis and site-directed mutagenesis showed that the N-terminal Slp (synaptotagmin-like protein) homology domain of Slac2-a specifically binds Rab27A/B isoforms and that the C-terminal half directly binds the globular tail of myosin Va. The tripartite protein complex (Rab27A· Slac2-a·myosin Va) in melanoma cells was further confirmed by immunoprecipitation. The discovery that myosin Va indirectly recognizes its cargo through Slac2-a, a novel Rab27A/B effector, should shed light on molecular recognition of its specific cargo by class V myosin.

Griscelli syndrome is an autosomal recessive disorder characterized by pigmentary dilution and is occasionally associated with a hemophagocytic syndrome (type 2). We present a 13-year-old girl with Griscelli syndrome type 2, who developed a hemophagocytic syndrome along with marked muscle weakness and elevated plasma creatine kinase. Muscle biopsy showed massive inflammatory changes in some fascicles, while other fascicles were relatively spared. Clinical symptoms and biopsy changes resolved after immunosuppression and allogeneic hematopoietic cell transplantation. Our results suggest that muscle involvement should be considered in patients with hemophagocytic syndrome to ensure proper treatment.

1. IntroductionThe myosin family of actin-based molecular mo-tors consists of 15 known classes that are structurallydistinct based on comparisons of the primary struc-ture of the motor domains of the known myosinheavy chain genes [1^3]. Information regarding thefunction and/or biochemical properties of most ofthese myosin classes is sparse relative to the well-characterized class II and class I myosins; neverthe-less, the range of proposed functions for these myo-sins is already remarkably broad [1]. There are anumber of recent reviews that provide an overviewof the rapidly growing myosin gene family [1,4^8].Among the best characterized and functionally di-verse of the recently discovered myosin classes arethe class V myosins, the focus of this review (forother reviews see [9^11]).Myosin-V was initially characterized as an unusualcalmodulin binding protein from brain with a num-ber of myosin-like biochemical properties [12^14].Subsequently, myosin-V heavy chain genes werecloned from mouse, yeast and chicken, thus de¢ningthe ¢fth class of actin-based motors [15^19]. Studiesof the mouse and yeast class V myosins provided the¢rst insights regarding the cellular function of myo-sin-V. Phenotypes of the mutant dilute mouse andthe temperature-sensitive yeast mutant, myo2-66 ledto the hypothesis that class V myosins may functionin cell polarity and membrane tra⁄cking [15,16].Moreover, mutations in the human ortholog of thedilute heavy chain gene cause Griscelli syndrome, arare recessive disease characterized by pigmentarydilution and in most, but not all cases immunode¢-ciency [20^22]. Neurological disorders have also beenreported in Griscelli syndrome patients [22,23]. Sincethese ¢rst studies, a great deal has been learnedabout the biochemistry, biophysics and cellular func-tion of the class V myosins. This review will discussthe emerging evidence that myosin-V is a processiveactin-based motor that has multiple functions in thecell ranging from mRNA transport, cell polarity andmembrane tra⁄cking.There are currently nine complete myosin-V heavychain sequences known (Fig. 1). Analysis of the twocompleted eukaryotic genomes of Saccharomyces ce-revisiae and Caenorhabditis elegans reveals that yeasthave two class V myosins, while C. elegans has asingle class V myosin heavy chain gene. In verte-brates, there are at least three distinct subclasses ofmyosin-V. The three most closely related heavy chainsequences, that of chicken brain myosin-V, the

Mutations of the gene encoding myosin V can produce a dilute or silvery hair color and various neurologic defects in mice and patients with Griscelli syndrome, leading to speculations that the myosin V motor protein plays a critical role in transporting melanosomes within melanocytes and neurosecretory vesicles within neurons. Therefore, we investigated the in vitro expression of myosin V in cultured normal human melanocytes, keratinocytes, and dermal fibroblasts using reverse transcriptase-polymerase chain reaction and northern blot analysis. Subcellular distribution of myosin V and proximity to actin bundles and melanosomes were determined by double indirect immunofluorescence labeling and immunogold electron microscopy. In all studied cells myosin V is expressed and treatment of melanocytes with the cyclic AMP-inducer 3-isobutyl-1-methylxanthine causes an induction of the myosin V message. In all cells myosin V colocalizes with actin bundles, concentrating in the subcortical cell zone. In the melanocyte it is closely associated with melanosomes. Quantitative analysis of myosin V labeling in melanocytes reveals a significantly higher (p < 0.005) presence of myosin V in the periphery of dendrites. These results suggest that myosin V is important in melanosome transport in human melanocytes. Possible roles in the other skin cells remain to be elucidated.

Myelodysplastic syndrome (MDS) in children has been reported to be associated with various constitutional anomalies; however, it has not been described previously in patients with Griscelli syndrome (GS). In this report, we present a case with GS and refractory anemia with an excess of blasts. We believe that careful evaluation of peripheral blood and bone marrow could increase the number of patients who are found to have GS-associated MDS.

To the Editor: In a recent report, Anikster et al. (2002) identified a RAB27A (MIM 603868) deletion in a kindred with Griscelli syndrome (GS) (MIM #214450). Several patients from this kindred displayed neurological manifestations related to the hemophagocytic syndrome (HPS). On the basis of their study, the authors suggest “that the neurological involvement in these patients with GS occurs secondarily to the hemophagocytic syndrome and that patients with primary CNS complications and MYO5A (MIM 160777) mutations have a related disorder, namely, Elejalde syndrome.” This assertion is certainly correct but surprisingly is presented as new and as an “alternative explanation.” Several previously published reports have unequivocally established that neurological manifestations occurring in patients with GS and caused by RAB27A mutation are related to lymphocyte infiltration of the CNS (Menasche et al. 2000; Pastural et al. 2000; de Saint Basile and Fischer 2001), whereas patient(s) with GS caused by MYO5A mutations exhibit a primary neurological disease, potentially described as Elejalde syndrome, and is unrelated to the hematopoietic lineage, as also observed in Myo5a mutant dilute mice (Pastural et al. 1997, 2000; Sanal et al. 2000; de Saint Basile and Fischer 2001; Ivanovich et al. 2001). The common finding of both conditions is albinism that results from the same mechanism—a defective release of melanosome content to neighboring cells, such as keratinocytes in the skin. MyoVA and Rab27A have been shown to interact in the same molecular pathway, resulting in melanosome transport on actin filament to dock at plasma membrane (Marks and Seabra 2001; Hume et al. 2002; Provance et al. 2002; Seabra et al. 2002). There should not be any confusion left, since patients with partial albinism and manifestations of HPS, with or without neurological involvement, should be screened for RAB27A mutations and treated accordingly, whereas those with partial albinism and a primary neurological disease without HPS should be screened for MYO5A mutations, as discussed elsewhere (Menasche et al. 2000) There are numerous examples of conditions grouped under the same umbrella name (such as “Gaucher disease type I to III”) because of shared biological mechanisms, but that have different outcomes and treatments. Griscelli syndromes 1 and 2 are other examples. Incidentally, in table 1 of the Anikster et al. report, the dilute and ashen murine models have been inverted, potentially causing some confusion.

Perforin is a prototype effector molecule of cytotoxicity-mediated immune cells. Following cell triggering, perforin inserts into the plasma membrane and undergoes polymerization to form pores that may lead to osmotic lysis of target cells and allow granzymes and other granule components to enter the target cells and to initiate apoptotic events. The perforin deficiency has recently been identified as an underlying cause of familial hemophagocytic lymphohistiocytosis (FHL) (Ref. 1xPerforin gene defects in familial hemophagocytic lymphohistiocytosis. Stepp, S.E. et al. Science. 1999; 286: 1957–1959Crossref | PubMed | Scopus (715)See all References1), a severe inherited human disorder characterized by a major immune dysregulation that invariably leads to death of patients unless treated with bone-marrow transplantation.In a recent Trends article2xPerforin: more than just an effector molecule. Stepp, S.E. et al. Immunol. Today. 2000; 21: 254–256Abstract | Full Text | Full Text PDF | PubMed | Scopus (96)See all References2, Stepp and colleagues offered a provocative hypothesis on the possible role of perforin not only as an effector molecule, but also as an immune regulator. There is, in fact, ample experimental evidence in the literature over the past six years to show that absence of perforin function shifts the antigen kinetics in various viral and intracellular bacteria infections but also has an influence on the half-life of antigen presenting cells that present new peptides via class I-MHC (Ref. 3xMolecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Kagi, D. et al. Annu. Rev. Immunol. 1996; 14: 207–232Crossref | PubMed | Scopus (491)See all References3). Perforin also influences the destruction of solid peripheral tissue cells and the release of possible ‘ignored’ self-antigens; therefore perforin might influence autoimmune processes. We feel that the Trends article assigning a regulatory role to perforin might be misleading. Immune regulation is a common term that has been suffered from misuse too many times; in this context, perforin should not be added.In the case of FHL, perforin deficiency results in a severe immune dysregulation, but this effect should not necessarily be explained on the ground of a perforin-mediated regulatory effect. Indeed, the various pathological events that characterize both FHL and related immunodeficiencies, including Chediak–Higashi and Griscelli syndrome4.xPartial albinism with immunodeficiency (Griscelli syndrome). Klein, C. et al. J. Pediatr. 1994; 125: 886–895Abstract | Full Text | Full Text PDF | PubMed | Scopus (160)See all References, 5.xGriscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Pastural, E. et al. Nat. Genet. 1997; 16: 289–292Crossref | PubMed | Scopus (293)See all References, both characterized by the inability to release perforin-containing granules, can reflect the impaired effector function of perforin. The following explanation appears more likely: the whole clinical picture would stem from the inability of cytolytic effector cells to clear the infecting pathogen. Although T-cell-mediated recognition of pathogen-derived peptides leads to T-cell activation and clonal expansion, the resulting cells fail to kill the infected cells and thus to remove the source of antigen stimulation. On the other hand, this persistent, antigen-driven T-cell activation results in the production of large quantities of cytokines, including interferon γ (IFN-γ) and granulocyte–macrophage colony-stimulating factor (GM-CSF), two important macrophage activators. The sustained macrophage activation (and recruitment) results in tissue infiltration and in the production of high levels of tumour necrosis factor α (TNF-α), interleukin 1 (IL-1) and IL-6, which play a major role in the various clinical symptoms and tissue damage. Remarkably, the so-called ‘accelerated phases’ characteristic of Chediak–Higashi and Griscelli syndrome, display similar pathologic and clinical features. A different picture occurs in the X-linked lymphoproliferative disease (XLP) (Ref. 6xThe X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Sayos, J. et al. Nature. 1998; 395: 462–469Crossref | PubMed | Scopus (640)See all References6): in these patients, the inability to control Epstein–Barr virus (EBV) infections is consequent to a major dysfunction of 2B4 receptor, which exerts inhibitory instead of activating function7xX-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein–Barr virus-infected cells. Parolini, S. et al. J. Exp. Med. 2000; 192: 337–346Crossref | PubMed | Scopus (325)See all References7.In conclusion, the self destructive reactions occurring in FHL and related immunodeficiencies would involve the lack of perforin viewed as an effector molecule rather than as a molecule regulating the immune response.