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CD45-Deficient Severe Combined Immunodeficiency Caused By CD45-deficient severe combined immunodeficiency caused by uniparental disomy Joseph L. Robertsa, Rebecca H. Buckleya,b,1, Biao Luoc,d, Jianming Peid, Alla Lapidusc, Suraj Peric, Qiong Weie, Jinwook Shina, Roberta E. Parrotta, Roland L. Dunbrack, Jr.e, Joseph R. Testad,f, Xiao-Ping Zhonga,b, and David L. Wiestf aDepartment of Pediatrics and bDepartment of Immunology, Duke University Medical Center, Durham, NC 27710; and dCancer Biology Program, eDevelopmental Therapeutics Program, fBlood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, and cCancer Genome Institute, Fox Chase Cancer Center, Philadelphia, PA 19111 Contributed by Rebecca H. Buckley, March 16, 2012 (sent for review November 16, 2011) Analysis of the molecular etiologies of SCID has led to important mesoderm-derived lymphocytes and ectoderm-derived buccal epi- insights into the control of immune cell development. Most cases of thelial cells, suggesting that the duplication occurred before germ- SCID result from either X-linked or autosomal recessive inheritance layer specification. of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of Results SCID in a patient known to lack the protein-tyrosine phosphatase SCID Patient Lacks CD45 Expression. Flow cytometric analysis of the CD45, we used SNP arrays and whole-exome sequencing. The patient’s peripheral blood lymphocytes at presentation at age 10 patient’s mother was heterozygous for an inactivating mutation mo revealed normal numbers of B and NK cells but dramatically in CD45 but the paternal alleles exhibited no detectable mutations. reduced numbers of T cells (Table 1). Moreover, the few T cells The patient exhibited a single CD45 mutation identical to the ma- present were found to be nonfunctional as they were unresponsive ternal allele. Patient SNP array analysis revealed no change in copy to mitogenic stimulation (Fig. 1B). Serum IgM, IgA, and IgE were number but loss of heterozygosity for the entire length of chromo- undetectable or low (Table 1). Cell-surface CD45 protein expres- some 1 (Chr1), indicating that disease was caused by uniparental sion was lacking on all leukocytes following staining with Abs disomy (UPD) with isodisomy of the entire maternal Chr1 bearing recognizing CD45 RA, CD45RO, or all CD45 isoforms (Fig. 1A CD45 the mutant allele. Nonlymphoid blood cells and other meso- and Table 1), consistent with the previous finding of absent bone derm- and ectoderm-derived tissues retained UPD of the entire marrow leukocyte CD45 expression at the referring hospital. CD45 maternal Chr1 in this patient, who had undergone successful bone is essential for T-cell development and T-cell receptor (TCR) marrow transplantation. Exome sequencing revealed mutations in signal transduction (9, 10), and has previously been identified in two seven additional genes bearing nonsynonymous SNPs predicted to fi fatal cases of SCID (3, 4). The patient in this report underwent a have deleterious effects. These ndings are unique in representing successful T-cell–depleted haploidentical maternal bone marrow a reported case of SCID caused by UPD and suggest UPD should be stem-cell transplant without preconditioning or posttransplantation considered in SCID and other recessive disorders, especially when graft-versus-host disease (GVHD) prophylaxis at age 10 mo and the patient appears homozygous for an abnormal gene found in currently has normal numbers of B and NK cells, as well as normal only one parent. Evaluation for alterations in other genes affected numbers of CD45-expressing, functional T cells at 5 y posttrans- by UPD should also be considered in such cases. plantation (Fig. 1B and Table 1). The loss of CD45 expression in the patient was not the result of T lymphocyte | T cell receptor | signaling a defect in transcription, because the level of CD45 mRNA in the patient was only slightly decreased relative to that of controls (Fig. CID is a syndrome characterized by absent T- and B-lympho- 1C). Sanger sequencing revealed that the patient’s mother was Scyte function that is uniformly fatal in infancy without immune heterozygous for a nonsense mutation at position 1618 (1618A > reconstitution (1, 2). Mutations in several different genes impor- T) of the coding sequence in exon 14 of the CD45 gene that cre- tant for normal T-cell development, function, or survival have been ated a stop codon at amino acid 540 (K540X); however, no mu- shown to cause SCID, with a majority of reported cases caused tations were observed in the coding region of either paternal CD45 IL2RG IL7RA ADA JAK3 RAG1 RAG2 by mutations in , , , , , ,or allele (Fig. 2). Surprisingly, the patient was homozygous for the DCLRE1C (1, 2). Rare defects in six other genes have also been 1618A > T mutation observed in the maternal allele (Fig. 2). This described, including two fatal cases caused by mutations in the finding suggested that either one copy of paternal Chr1 bore a gene encoding the CD45 protein tyrosine phosphatase (1, 3, 4). microdeletion eliminating the CD45 locus, or the patient inherited Uniparental disomy (UPD) refers to the inheritance of two two copies of the mutant maternal CD45 allele. copies of a chromosome, or segment of a chromosome, from one parent. UPD was first observed in 1988 in a patient with cystic SCID Is Caused by Duplication of the Mutant Maternal CD45 Allele fibrosis who had inherited two maternal copies of chromosome 7 Because of UPD of Chr1. To distinguish these possibilities, SNP bearing a mutant CFTR allele (5, 6). Since that report, UPD has arrays were performed on genomic DNA from EBV lines derived been found to underlie a number of diseases, including Prader– from B lymphocytes of the parents and patient. These analyses Willi, Angelman, and Beckwith–Wiedermann syndromes (7). UPD causes a genetic disorder either through inheritance of two mutant copies of a gene, thereby enabling a recessive mutation to manifest, Author contributions: J.L.R., R.H.B., J.R.T., and D.L.W. designed research; J.S. and R.E.P. or through inheritance of two silenced copies of an intact allele (8). performed research; B.L., J.P., A.L., S.P., Q.W., R.L.D., and X.-P.Z. contributed new re- UPD has not previously been reported as a mechanism of in- agents/analytic tools; J.L.R., R.H.B., B.L., J.P., A.L., S.P., Q.W., R.L.D., J.R.T., X.-P.Z., and D.L.W. analyzed data; and J.L.R. and D.L.W. wrote the paper. heritance in SCID. In the present report, we are unique in de- fl scribing an example of SCID caused by UPD, in which the first The authors declare no con ict of interest. surviving CD45-deficient SCID patient inherited two complete Data deposition: The data reported in this paper have been deposited in the Gene Ex- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE35674) copies of a single maternal Chr1 bearing a nonsense mutation in and the Database of Genotypes and Phenotypes (dbGaP), www.ncbi.nlm.nih.gov/gap re- the exodomain of CD45. This complete isodisomy of Chr1 with pository (accession no. phs000479.v1.p1). resultant loss of heterozygosity (LOH) was present in both 1To whom correspondence should be addressed. E-mail: [email protected]. 10456–10461 | PNAS | June 26, 2012 | vol. 109 | no. 26 www.pnas.org/cgi/doi/10.1073/pnas.1202249109 Downloaded by guest on September 24, 2021 Table 1. Patient Immune phenotype and function Patient At presentation Most recent Controls Serum Ig level* IgG† 516 604 192–515 IgA 0 12 12–31 IgM 9 9 39–92 ‡ Lymphocyte subpopulation CD45+ 4 (0.4) 581 (51.9) 1,500–7,000 + CD3 31 (2.9) 596 (53.2) 1,111–5,183 + Percent of CD3 that are CD45RO (%) ND (55.8) (24.9–42.5) Percent of CD3 that are CD45RA+ (%) ND (22.8) (27.6–46.2) CD4+ 24 (2.3) 273 (24.4) 675–3151 + Percent of CD4 that are CD45RO (%) ND (58.1) (24.9–42.5) + Percent of CD4 that are CD45RA (%) ND (21.2) (27.6–46.2) CD8+ 3 (0.3) 174 (15.5) 431–2012 Percent of CD8 that are CD45RO+ (%) ND (41.1) (24.9–42.5) + Percent of CD8 that are CD45RA (%) ND (32.5) (27.6–46.2) + TCRαβ 21 (2) 468 (41.8) 1,855–3,199 CD20+ 854 (80.9) 516 (46.1) 144–671 + CD16 71 (6.7) 31 (2.8) 152–709 Proliferative stimulus§ Medium 128 228 693 ± 825 Candida ND 3,539 5,937–59,291 Tetanus ND 8,486 13,004–68,696 ND, not determined. *Values are expressed as mg/dL (IgG, IgA, IgM) or U/mL (IgE). Normal values are the 95% confidence intervals for 9- to 12-mo-old control subjects. † The patient was receiving intravenous immune globulin when the IgG levels were measured. ‡ Values are expressed as cells/mm3 or (percentage of lymphocytes). Control values are the 95% confidence intervals for 1,550 normals. §Values are cpm [3H]thymidine incorporation. Controls values are the mean ± SD of responses in 167 normals. demonstrated that there was no change in copy number across the To identify such alleles, exome sequencing was performed on CD45 locus on Chr1 (Fig. 3A), indicating that the patient had DNA samples from mother, father, and patient. Using the ma- either inherited two entire copies of maternal Chr1 or two copies ternal alleles for UPD analysis, we identified 36 homozygous of the region encompassing the maternal CD45 mutation. The SNPs, all of which were located on Chr1 (Table 2). Conversely, no allele profiles from the whole-genome array analysis revealed paternal alleles of UPD from any chromosome were identified.
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