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Mutations in the Gene Encoding the PML Nuclear Body Protein Sp110

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Mutations in the Gene Encoding the PML Nuclear Body Protein Sp110 BRIEF COMMUNICATIONS Mutations in the gene encoding hVOD (Table 1) who met the clinical criteria for VODI (see Supplementary Methods online). The clinical correlates of immuno- the PML nuclear body protein deficiency included Pneumocystis jerovici infection, enteroviral infec- tion or mucocutaneous candidiasis, but there was no evidence of Sp110 are associated with mycobacterial infection. Hepatic VOD was verified by biopsy in at least one individual in each sibship and was indistinguishable clinically immunodeficiency and hepatic and pathologically from the sinusoidal obstruction syndrome described after hematopoietic stem cell transplantation. veno-occlusive disease The B cell immunodeficiency was characterized by evolving severe Tony Roscioli1–3, Simon T Cliffe2, Donald B Bloch4, hypogammaglobulinemia, absent memory (CD19+ CD27+ IgD–) Christopher G Bell2, Glenda Mullan2, Peter J Taylor2, B cells and tonsillar lymph nodes, and circulating CD19+ B cell Maria Sarris5, Joanne Wang6, Jennifer A Donald7, numbers and percentages within the normal range. Absence of lymph Edwin P Kirk8,9, John B Ziegler9,10, Ulrich Salzer11, node germinal centers and tissue plasma cells have been noted as a http://www.nature.com/naturegenetics George B McDonald6, Melanie Wong12, Robert Lindeman2,5,13 consistent finding in autopsies that have been reported on 12 affected & Michael F Buckley1,2,13 individuals, consistent with a block in B cell differentiation (M.W., personal communication). The T cell immunodeficiency was char- We describe mutations in the PML nuclear body protein acterized by reduced numbers of memory (CD4+ CD45RO+ CD27–) Sp110 in the syndrome veno-occlusive disease with T cells (1–2%; normal is 440%) and low or reduced intracellular immunodeficiency, an autosomal recessive disorder T cell cytokine expression (IFNg,1À4% (reference range, 25À30%); of severe hypogammaglobulinemia, combined T and IL2, 1–3% (12–32%); IL4 1–2% (4–7%) and IL10 1–2% (1–6%)) after B cell immunodeficiency, absent lymph node germinal stimulation with phorbol myristate acetate (PMA) and ionomycin. centers, absent tissue plasma cells and hepatic veno-occlusive CD4 and CD8 T cell numbers and percentages and T cell proliferation disease. This is the first report of the involvement of a assays were normal. nuclear body protein in a human primary immunodeficiency We performed homozygosity mapping in four affected individuals Nature Publishing Group Group Nature Publishing 6 and of high-penetrance genetic mutations in hepatic and their parents from families A, B and C after obtaining approval from the relevant institutional ethics committees and informed 200 veno-occlusive disease. © written consent. We mapped VODI to chromosome 2q36.3-37.1. Hepatic veno-occlusive disease with immunodeficiency syndrome Fine-mapping studies identified a conserved haplotype of three (VODI, OMIM235550) is an autosomal recessive primary immuno- short tandem repeat (STR) markers spanning a genomic interval deficiency associated with hepatic vascular occlusion and fibrosis1. of 1.422 Mb (Fig. 1a,b) that contained the gene SP110 (encoding VODI has an estimated frequency of 1:2,500 live births in the Sydney 110-kDa Speckled). SP110 is an immunoregulatory gene expressed in Lebanese population, with 19 cases identified over a period of T and B lymphocytes, lymph nodes, spleen and liver2,3;therefore,we 30 years. VODI is associated with an 85% mortality if unrecognized screened its coding exons for mutations by DNA sequencing. and untreated with intravenous immunoglobulin and Pneumocystis Mutation screening (Supplementary Table 1 and Supplementary jerovici prophylaxis. The association of an immunodeficiency with Methods) identified a homozygous single-base deletion, 642delC hepatic veno-occlusive disease (hVOD) has not been recognized in (P214PfsX15), in exon 5 in affected individuals from families A–C other classes of immunodeficiency, suggesting that hVOD is not a and subsequently in family D (Fig. 1c). No living affected individuals secondary event but is a primary feature of VODI. were available from family E, but the consanguineous parents and We identified six children from five families of Lebanese ethnicity unaffected children were shown to share a heterozygous single-base who presented between 3–7 months of age with either a combined T deletion, 40delC (Q14SfsX25) in exon 2 on a different haplotype and B cell immunodeficiency and/or a personal or family history of background from families A–D. We confirmed that this mutation was 1Centre for Vascular Research, University of New South Wales, Sydney 2052, Australia. 2Molecular & Cytogenetics Unit, Department of Haematology and Genetics, Prince of Wales Hospital, Sydney 2031, Australia. 3Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital, University of Sydney, Sydney 2050, Australia. 4Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA. 5School of Medical Sciences, University of New South Wales, Sydney 2052, Australia. 6Fred Hutchinson Cancer Research Center and University of Washington Schools of Medicine & Pharmacy, Seattle, Washington 98109, USA. 7Department of Biological Sciences, Macquarie University, Sydney 2109, Australia. 8Department of Medical Genetics, Sydney Children’s Hospital, Sydney 2031, Australia. 9School of Women’s & Children’s Health, University of New South Wales, Sydney 2052, Australia. 10Department of Immunology & Infectious Diseases, Sydney Children’s Hospital, Sydney 2031, Australia. 11Division of Rheumatology and Clinical Immunology, Medical Centre, University Hospital, Hugstetterstr. 55, 79106 Freiburg, Germany. 12Department of Immunology and Allergy, Children’s Hospital, Westmead 2145, Australia. 13These authors contributed equally to this work. Correspondence should be addressed to T.R. ([email protected]). Received 27 October 2005; accepted 14 March 2006; published online 30 April 2006; doi:10.1038/ng1780 620 VOLUME 38 [ NUMBER 6 [ JUNE 2006 NATURE GENETICS BRIEF COMMUNICATIONS Table 1 Summary of clinical and laboratory data in the VODI families Percentage circulating Serum Ig (g l–1) cells Tcell Age Memory T T cell PHA/ConA cytokine Individual Sex (months) Presentation IgM IgG IgA B T & B cells subsets Response production Current clinical state A II.1 F 5 Immunodeficiency, 0.16 0.5 o0.07 N N – N N – Deceased; recurrent hVOD thrombocytopenia post HSCT and hVOD B II.1 M 7 Immunodeficiency 0.1 0.2 0.07 N N Decreased N N Impaired Well B II.2 F 6 Hepatosplenomegaly 0.09 o0.33 o0.07 17 58 Decreased N N Impaired Mild aminotransferase and ascites elevation C II.1 F 4 Hepatosplenomegaly 0.2 0.55 o0.07 8 79 Decreased N N Impaired Chronic liver disease and and thrombocytopenia portal hypertension D II.1 M 3 hVOD 0.05 o0.33 o0.07 23 79 Decreased N N Impaired Deceased; hemophagocytic syndrome post hepatic transplant for hVOD E I.1 M 3 Immunodeficiency & 0.05 0.8 o0.06 N N – N N – Deceased; enteroviral thrombocytopenia and Pneumocystis jerovici infection PHA: phytohemagglutinin; ConA: concanavalin A; HSCT: hematopoietic stem cell transplantation. http://www.nature.com/naturegenetics homozygous in DNA extracted from archival tissue from EII.1. We did from 642delC homozygous patients compared with their heterozygous not detect either mutation in 50 unrelated Lebanese controls. In siblings and familial controls (Fig. 2j). We did not see any corre- addition, we did not detect any mutations in the coding regions of sponding changes in mRNA levels in the evolutionarily related, SP110 in 89 isolated cases of common variable immunodeficiency of physically adjacent genes SP100 and SP140. Long-range PCR per- European or Middle Eastern origin4. formed on random hexamer-primed cDNA generated from indivi- Sp110 nuclear staining was absent in EBV-transformed B lympho- duals with VODI and heterozygotes showed no evidence of exon cytes from an affected individual with the homozygous 642delC skipping (data not shown). These data are consistent with absence of mutation in exon 5. Sp100 staining was consistent with normal Sp110 without disruption of the PML nuclear body in individuals PML nuclear body numbers (Fig. 2a–h). Protein blot analysis using with VODI. a rat anti-Sp110 antiserum confirmed the absence of the two major Given the association between mutations in SP110 and hVOD, Nature Publishing Group Group Nature Publishing 6 isoforms, Sp110b and Sp110c, in affected cell lines (Fig. 2i). A we were interested to determine if there was an association between quantitative TaqMan real-time PCR assay demonstrated significantly Sp110 alleles and the risk of hVOD after hematopoietic stem cell 200 © reduced SP110 mRNA levels in B lymphoblastoid cell lines established transplantation. We performed a targeted SP110 SNP association study using 69 SNPs with an average inter- SNP distance of 0.826 kb in a cohort of 47 a Family A Family BFamily C Family D Family E affected individuals and 62 controls who had D2S133 1 2 4 2 5 4 5 4 4 5 2 4 received standardized myeloablative condi- D2S2354 1 0 9 0 2 3 0 3 9 9 9 0 5 S2S362 2 1 2 1 2 1 2 1 4 1 2 3 3 2 3 2 tioning therapy .Measuresofassociation AFMA283YB1 3 1 2 1 3 1 1 1 4 1 2 4 4 2 4 2 AFMA289YE1 2 1 2 1 3 1 1 1 2 1 2 3 7 4 3 4 between hVOD and alleles of SP110 did not AFMB329WE9 5 4 3 4 1 4 4 4 1 4 3 2 2 5 3 5 AFM277WG9 3 2 4 2 3 2 3 2 4 2 1 2 2 3 1 3 reach statistical significance. D2S396 9 6 8 6 7 6 7 6 9 6 7 6 na na na na AFMC004XH5 1 3 2 3 2 3 1 3 4 3 4 3 2 5 6 5 AFM324VC9 2 3 4 3 2 5 1 5 3 3 1 3 7 5 6 5 D2S206 6 2 8 2 0 5 8 3 6 5 8 9 D2S2202 8 8 7 8 6 6 6 6 6 6 6 6 D2S133 2 2 4 4 5 4 5 4 Figure 1 SP110 mapping and mutation analysis.
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