| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP)
Introduction
Results
Mutation screening in the SH2D1A and TNM1 genes of XLP families or patients
Mutations in XLP patients with preceding EBV infections and IM
SH2D1A mutation in EBV-negative XLP patients with dysgammaglobulinaemia and/or early onset NHBL
Discussion
Materials And Methods
Patients
Haplotype analysis in XLP family 03
PCR reactions and sequencing analysis
Southern blot analysis
EBER in situ hybridization
EBV PCR
Acknowledgements
References
Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP)
Received July 2, 1999; Revised and Accepted September 9, 1999
DDBJ/EMBL/GenBank accession no. AF10072
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in ~70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.
INTRODUCTION
X-linked lymphoproliferative disease (XLP; MIM 308240) is an inherited immunodeficiency due to a primary T cell abnormality, which in most cases exacerbates following exposure to Epstein-Barr virus (EBV) (1-3). EBV infection in males with the defective XLP gene may lead to severe and often fatal infectious mononucleosis (IM) (58%), lymphoma, mostly of B cell origin (30%), dysgammaglobulinaemia (increased IgM and/or low IgG) (31%) and other less frequent manifestations (2). Although EBV infection preceded the onset of XLP manifestations in most cases, 27 of 272 patients (10%) exhibited an XLP phenotype without prior EBV infection. Malignant lymphomas were part of the first manifestation in 18 of 272 cases (2,4). Dysgammaglobulinaemia has been found in 17 of 32 XLP males (53%) who have never been exposed to EBV (2,5).
In a high percentage, malignant lymphomas in XLP are non-Hodgkin lymphomas (NHLs) of B cell origin, although T cell NHL and four cases of Hodgkin lymphomas have been described (6). Localization of the B cell lymphomas is extranodal in the ileocoecal region in 76% of cases. Onset of malignant lymphomas occurs at a mean age of 6 years, compared with an onset of 8 years in the general population (6).
A novel gene, SH2D1A, mutated in XLP families has recently been identified by a positional cloning and a functional cloning approach (7,8). The protein of 128 amino acids, encoded by four exons, has only one SH2 domain, containing 90 amino acids. Expression of the 2.5 kb SH2D1A transcript has been demonstrated in lung, spleen, colon and thymus, tissues with a high abundance of immunocompetent cells. Expression was noted in all major T cell subsets, thus indicating a defective CD4+ and CD8+ T lymphocyte response in XLP patients. Controversial data were published on expression in B cells. By RT-PCR, SH2D1A expression has been found in EBV-transformed B cells, while no expression could be detected by northern blot assay in FACS-sorted B cells derived from healthy donors (7-9).
The SH2 domain of SH2D1A interacts with a phosphotyrosine residue in the cytoplasmic part of signalling lymphocyte activating molecule (SLAM) (8,10) and also with the cytoplasmic part of 2B4 (11,12). SLAM and 2B4 are type I transmembrane receptors with two immunoglobulin-like domains each (10-14). While SLAM is expressed in T and B cells (10,13,14), 2B4 is mainly expressed in T cells and natural killer cells (11,12). Activation of SLAM or 2B4 recruits SHP2, an SH2 domain-containing tyrosine phosphatase, to their cytoplasmic domains. SH2D1A is a natural inhibitor of SLAM/SHP2 and 2B4/SHP2 binding (8,11) and thus regulates activation of SHP2. Whether SH2D1A also blocks the described binding of SHIP to SLAM is so far unclear (15). For SHP2, a positive modulatory role on cell proliferation by activating the MAP kinases has been proposed (16). In XLP patients lack of inhibition of the SLAM/SHP2 and similarity of the 2B4/SHP2 interaction and the subsequent activation of the MAP kinases may lead to an uncontrolled immune response to EBV with the development of fatal IM.
Apart from larger genomic deletions, 13 mutations, including five nonsense mutations, in the SH2D1A gene of XLP families have been published (7-9). Three identified missense mutations affect evolutionarily and functionally conserved amino acids in the SH2 domain. Thus, aberrations in the SH2D1A gene have been shown to cause XLP. Aside from the finding of further SH2D1A mutations in XLP patients we now report mutations in patients with no evidence of EBV infection but with development of NHL between the ages of 1.5 and 2 years. This indicates that clinical manifestations of XLP are not strictly EBV related but that EBV may act as a potent trigger of a serious clinical manifestation of XLP, i.e. IM.
RESULTS
Mutation screening in the SH2D1A and TNM1 genes of XLP families or patients
Typical clinical features of patients suffering from manifest or suspected XLP and/or NHL are summarized in Table 1. The gene mutated in XLP patients has been isolated by a positional cloning approach (7). It is localized in Xq24-25 at 7 kb distance from the TNM1 gene. The SH2D1A gene consists of four exons while the TNM1 gene contains 31 exons (Fig. 1). SH2D1A encodes a protein of 128 amino acids containing an SH2 domain, which is strongly conserved between human, mouse and rat. The flanking regions show a lesser degree of identity (7). In order to detect mutations in patients with XLP or suspected XLP, complete sequencing of the four exons and the promoter region of the SH2D1A gene was performed.
Figure 1. Gene organization of SH2D1A and TNM1.
Table 1. Phenotypes of the analysed XLP patients and patients with early onset non-Hodgkin lymphoma
| Family no. | Family history | Index patients | SH2D1A mutation | IM | EBV serology | EBV g-PCR EBER-ISH | Anaemia | Lymphoma | Dys-[gamma]-globulinaemia | Clinical history |
| 01 | 2 brothers with fatal IM (at age 1 and 3 years) | a | I1 G+1A | + | + | - | - | + (hypo-[gamma]- globulinaemia) | Stable under IVIG, age 10 years | |
| 02 | a (sporadic) | 539del 4bp | + | + | + | - | + (hypo-[gamma]-globulinaemia) | Stable, age 15 years | ||
| 03 | 4 brothers with fatal IM (all died at age 2-5 years) | 2 brothers: | ||||||||
| a | Y100X | + | + | - | - | + | Died after fatal IM at age of 5 years | |||
| b | Y100X | - | - | - | - | + (elevated IgM) | Healthy at age 1 year, SCT planned | |||
| 04 | 2 brothers: | |||||||||
| a | nf | + | + | + | - | + (IgA deficiency) | Stable, age 18 years | |||
| b | nf | + | + | + | - | + (IgA deficiency) | Stable, age 13 years | |||
| 05 | 3 brothers: | |||||||||
| a | nf | ? | ? | - | - | - | Died at age 8 years (varicella, pneumonia) | |||
| b | nf | + | + | - | NHL | + (IgG subclass deficiency) | Died at age 11 years (NHL) | |||
| c | nf | + | + | - | - | + (IgG subclass deficiency) | Recurrent infections, age 10 years | |||
| 06 | 1 uncle died at 4 years (hepatosplenomegaly, fever, anaemia) | 2 brothers: | ||||||||
| a | nf | + | + | + | - | + | Stable, age 17 years | |||
| b | nf | + | + | - | - | + | Stable, age 15 years | |||
| 07 | 2 uncles with malignant lymphoma and hypo-[gamma]-globulinaemia (death at 6 and 16 years) | a | T68I | + | + | - | -- | + (hypo-[gamma]-globulinaemia) | Stable under IVIG, age 13 years | |
| 08 | 6 affected males with fatal IM (0.5-2.5 years) | a | P101L | + | + | - | - | - | Died after fatal IM at age of 2.5 years | |
| 09 | 2 brothers: | |||||||||
| a | I2 G-1C | + | + | + | ? | + | Died at age 1 year after CT for virus-associated haemophagocytic syndrome | |||
| b | I2 G-1C | - | - | - | + | NHL | + | Stable under CT, age 2 years | ||
| 10 | 2 brothers: | |||||||||
| a | del Ex1 | - | - | - | + | NHL | - | In remission, age 15 years | ||
| b | del Ex1 | - | - | - | + | NHL | - | In remission, age 10 years |
Details of families 07 and 08 have been published previously (7).
Mutations in XLP patients with preceding EBV infections and IM
We have recently described two missense mutations, T68I and P101L, in two well-characterized XLP families (7) (Tables 1 and 2, families 07 and 08). In two further XLP patients with a characteristic familial history of XLP and one sporadic XLP case, three different mutations were identified (Table 2).
Table 2. Mutations in the SH2D1A gene
| Family | Nucleotide position | ID | Comment | Type | Experimental evidence |
| 01 | I1 +1G->A | I1 G+1A | Deletion of nucleotides 144-436 including initiation site | Sp | SSCP, sequencing, RT-PCR |
| 02 | 539delAAAA | 539del4bp | Frameshift (stop after 39 bp) | FS | SSCP, sequencing |
| 03 | T599A | Y100X | Tyr->Stop | NS | SSCP, sequencing |
| 07a | C502T | T68I | Thr->Ile | MS | SSCP, sequencing |
| 08a | C601T | P101L | Pro->Leu (interaction with SLAM) | MS | SSCP, sequencing |
| 09 | I2 -1G->A | I2 G-1A | Use of a cryptic splice site in exon 3 | Sp | Sequencing, RT-PCR |
| 10 | del exon 1 | del ex1 | Deletion of exon 1 | Del | PCR, sequencing, hybridization |
aSee ref. 7.
A novel nonsense mutation (Y100X) could be identified in a Spanish family (03) with six affected males dying in childhood after fulminant mononucleosis (Fig. 2). A splice site mutation, I1 G+1A, in family 01 affects the donor splice site of exon 1. The aberrant RNA transcript, missing the 3[prime] part of exon 1 and the start codon, could be detected by RT-PCR in unaffected controls. The mutated splice site in the index patient has a lower affinity for the donor site in exon 2 and use of a cryptic splice site located in the 5[prime] end of exon 1 is preferred (Fig. 3). In a sporadic case of XLP (family 02), a frameshift deletion, causing a stop mutation after 39 bp, was identified.
Figure 2. Stop mutation in family 03. (a) Pedigree with haplotype. (b) Stop mutation T599A (Y100X) revealed by direct sequencing (mutation above, wild-type sequence below).
Figure 3. Aberrant splicing products and usage of cryptic splice sites. Consequences of the splice site mutations given in Table 2 are shown.
No mutation could be identified in family 06 showing a clinical history and phenotype suggestive of XLP. In this family two brothers showed symptomatic and serologically proven EBV infection and dysgammaglobulinaemia, while chronic anaemia was only observed in the elder brother. Up to the present ages of 17 and 15 years, respectively, both brothers have not developed any signs suggestive of lymphoma. There was no proof of an SH2D1A mutation in two further families (04 and 05) whose phenotype with severe EBV infections, dysgammaglobulinaemia and anaemia (family 04) or occurrence of NHBL (family 05), respectively, was highly suggestive of XLP. To exclude the possibility that mutations in the adjacent TNM1 gene might account for the SH2D1A-negative patients, mutation screening in the TNM1 gene was carried out, but also did not show any mutations.
SH2D1A mutation in EBV-negative XLP patients with dysgammaglobulinaemia and/or early onset NHBL
Haplotype analysis in family 03 was performed with the markers DXS424 and HPRT. A healthy boy (III-3) showed the same haplotype as his affected, deceased brother III-1 (Fig. 2a). Mutation analysis for the Y100X mutation, found in DNA from his deceased brother, confirmed the haplotype analysis (Fig. 2b). Clinical re-evaluation for XLP symptoms showed an EBV seronegative status and dysgammaglobulinaemia with increased serum IgM and decreased serum IgG.
In a patient with NHL, sequencing of exon 3 of the SH2D1A gene showed an acceptor splice site mutation at the 3[prime] end of intron 2. He has a negative clinical history for EBV, negative EBV serology and negative results for EBV PCR of peripheral blood samples and also for EBV encoded RNA (EBER) in situ hybridization on blood, tumour and lymph node sections (family 09, Tables 1 and 2). The nucleotide substitution from guanosine to cytosine at position -1 of intron 2 in the NHL patient hinders efficient splicing at this acceptor site. Instead, different cryptic splice sites in exon 3 are used. Thus, 4 and 55 bp of exon 3 are deleted from the SH2D1A cDNA, which was shown by direct sequencing (Fig. 3). None of the common translocations for Burkitt lymphoma could be found on cytogenetic analysis (family 09, Table 1).
Two brothers with early onset NHL and bronchiectasis were also screened for aberrations in the SH2D1A gene (family 10, Table 1). A deletion of exon 1 in the SH2D1A gene was found by PCR (Fig. 4 and Table 2) and confirmed by Southern blot analysis. Compared with controls, a 4.1 kb PstI fragment could not be observed in the patient and a dosereduction in the hybridization intensity in the mother proved the deletion (data not shown). Both brothers had no previous history of IM and were shown to be EBV negative as demonstrated by EBER in situ hybridization of bone marrow, tumour and lymph node samples and EBV PCR of peripheral blood samples (Table 1).
Figure 4. Deletion of exon 1 in brothers with early onset NHL. Exons 1 and 2 from the patients (family 10) were amplified, and the products obtained separated on an agarose gel. Lack of exon 1 in the patients was confirmed by Southern blot hybridization.
DISCUSSION
Most of the mutations identified so far, large genomic deletions, smaller intragenic deletions, nonsense mutations and splice site mutations, lead to premature arrest of protein synthesis and, therefore, result in a non-functional SH2D1A protein. The described missense mutations affect the evolutionarily conserved SH2 domain, which interacts with the phosphotyrosine pocket of SLAM.
Two different splice site mutations have already been described (7,8), one of them not yet proven to be deleterious. A C->G mutation at position -3 of the acceptor splice site of exon 2 resulted in the generation of three aberrant transcripts, causing truncated proteins, and the wild-type transcript (8). Together with the splice site mutations described here, four splice site mutations have been described in a total of 18 patients (7-9; this study). Additionally, five splice variants, which likely are non-functional, have been cloned by RT-PCR (GenBank accession nos AF100539-AF100543). The relatively high number of splice mutations and splicing variants might be a consequence of the weakly conserved splicing sites. Mutations present in the introns of the SH2D1A gene that have not yet been analysed might account for the failure to detect mutations in families 04 and 05. In family 06, the SH2D1A cDNA has also been sequenced, thus making a splice site mutation in this family unlikely. In the mutation-negative families 04, 05 and 06, there were two or even three brothers with a chronic disease phenotype and symptoms fitting the XLP diagnosis. Beyond the characteristic and serologically documented EBV infection in male patients (individuals 04a, 04b, 05b, 05c, 06a and 06b), these siblings had various, but within each family consistent, signs of dysgammaglobulinaemia, as seen in more detail in Table 1. However, development of an NHL was only observed in one of the three brothers of family 05, whereas anaemia as a non-obligatory sign of XLP occurred in families 04 and 06. The variety of clinical findings results in difficulty in determining a diagnosis of XLP at a given time point in the development of children or adolescents, where some of the deleterious symptoms are not yet apparent.
In three boys from families 09 and 10, NHL developed at an early age. Previous EBV infection can be excluded on the basis of a negative clinical history, negative serological findings and negative results of EBER in situ hybridization and EBV PCR studies. The finding of SH2D1A mutations in these patients suggests that NHLs can develop in XLP patients even without previous EBV infection. Twenty-two per cent of all lymphomas in XLP patients reported so far (18 of 82) occurred without evidence of prior EBV exposure (2,4,6,18). The low antibody response of XLP patients to EBV infection makes definite exclusion of EBV infection rather difficult. However, since the patients described in this paper were repeatedly analysed for the presence of viral DNA and RNA, an earlier EBV infection is very unlikely. These data may indicate that EBV does not play an obligatory role in the development of most, if not all, malignant lymphomas in XLP patients.
Whether the phenotype of XLP patients is due to an exaggerated immune response following EBV infection or whether it is based on an inefficiency of T cells to eliminate or to restrict EBV infection to a subgroup of B cells is not yet clear. The actions of SHP2 after its recruitment by SLAM and/or 2B4 are not completely resolved, although a modulation of the MAP kinase pathway has been shown repeatedly. Since the clinical phenotype of XLP with cytotoxic invasion of lymphoid tissues and their subsequent destruction seems to be more related to an exaggerated cytotoxic T cell response, lack of SH2D1A protein probably results in a proliferative signal to cytotoxic T cells. This signal might be enhanced after EBV infection by strong B and T cell proliferation. Single B cell clones might accumulate further mutations and achieve tumour properties. The finding of three EBV-negative patients with NHL suggests that this postulated process may also be independent of EBV, although a so far undetected trigger in these patients might have enhanced the proliferative signal.
MATERIALS AND METHODS
Patients
From 10 unrelated affected individuals with the XLP, XLP-suspected or NHBL phenotype, DNA was extracted from peripheral blood samples following standard protocols. Pedigrees, haplotype analysis and clinical data for families 01-03 have been described previously (19), as have those of family 06 (20) and families 07 (7) and 08 (22). Family 10 will be described in detail elsewhere (B. Strahm, K. Rittweiler, U. Duffner, O. Brandau, M. Orlowska-Volk, M.A. Karajannis, U. zur Stadt, M. Tiemann, A. Reier, M. Brandis, A. Meindl and C.M. Niemeyer, submitted for publication). Clinical and laboratory data for all families included in this study are summarized in Table 1.
Haplotype analysis in XLP family 03
Genomic DNA was prepared from peripheral blood of eight family members and analysed by multiplex PCR simultaneously using two polymorphic markers flanking the XLP gene proximally (DXS424, at Xq24-q25) and distally (HPRT, at Xq26.1). The primer sequences flanking the DXS424 locus are 5[prime]-CTAGTTGGAGGCTATGCAC-3[prime] and 5[prime]-GTTATCA-GTGTCAAGACAATTC-3[prime]. The sequences for the primers flanking the HPRT locus are 5[prime]-ATGCCACAGA TAATACAC-ATCCCC-3[prime] and 5[prime]-CTCTCCAGAATAGTTAGATGTAGG-3[prime].
PCR reactions and sequencing analysis
All four exons of SH2D1A (modified after ref. 7) and 31 exons of TNM1 (available on request) were amplified under the following conditions. After an initial denaturation for 5 min at 94°C, denaturation was at 94°C for 1 min, annealing at the exon-specific temperature for 1 min and extension at 72°C for 35 cycles. Amplified fragments from all exons were sequenced using BIG-dye terminator technology (Perkin-Elmer, Weiterstadt, Germany) and analysed on an ABI 377 sequencer. RT-PCR with SH2D1A-specific primers was carried out using the Advantage cDNA PCR kit (Clontech, Heidelberg, Germany), with an initial denaturation at 94°C for 5 min followed by 30 cycles of 94°C for 30 s and 68°C for 3 min. Primers were used in a nested set-up: AF (5[prime]-AAGCCCTTGGCAAGCTCGATC-3[prime]) and AR (5[prime]-AGTCCATTTCAGCTTTGACGAC-3[prime]) for the first round; BF (5[prime]-ACCAAGCTACTAAATTGCTGAGC-3[prime]) and BR (5[prime]-ATGATAGATGCTTCCATTACAGG-3[prime]) for the second amplification cycle. The TNM1 cDNA has been submitted to GenBank, accession no. AF10072.
Southern blot analysis
DNA from family 10 and a male and female control was digested with PstI and blotted onto a nylon membrane. The filter was hybridized with the SH2D1A cDNA under stringent conditions (0.1× SSC).
EBER in situ hybridization
Deparaffinized tissue sections were hybridized with digoxigenin-labelled EBER sense and antisense probes and stained with digoxigenin antibodies coupled to alkaline phosphatase (22).
EBV PCR
A nested PCR with primers TC58 (CAAGCCTAGGGGAGA), TC59 (TACGGACTCGTCTGG), TC60 (GGCCAGAGGTAA-GTGGACT) and TC61 (GACCGGTGCCTTCTTAGG) was performed.
ACKNOWLEDGEMENTS
We thank the patients and families who have contributed to this project. We gratefully acknowledge Prof. Dr D. Schendel (Department of Immunology at the GSF, München, Germany) for critical reading of the manuscript as well as Dr S. Garcia-Minaur (Hospital de Cruces, Baracaldo, Spain) for providing blood samples and DNA. This work has been supported by a grant from the BMBF (German Ministry for Education and Research).
REFERENCES
+To whom correspondence should be addressed. Tel: +49 89 5160 4467; Fax: +49 89 5160 4468; Email: alfons{at}pedgen.med.uni-muenchen.de
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