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Novel MAGT1 Mutation Found in the First Chinese XMEN in Hong Kong

Novel MAGT1 Mutation Found in the First Chinese XMEN in Hong Kong Hindawi Case Reports in Immunology Volume 2022, Article ID 2390167, 3 pages https://doi.org/10.1155/2022/2390167 Case Report Novel MAGT1 Mutation Found in the First Chinese XMEN in Hong Kong 1 1 1 2 Elaine Yuen Ling Au , Edmund Kwok Kwan Tung, Ricky Wai Ki Ip, and Philip Hei Li Department of Pathology, Queen Mary Hospital, Pok Fu Lam, Hong Kong Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, "e University of Hong Kong, Pok Fu Lam, Hong Kong Correspondence should be addressed to Elaine Yuen Ling Au; elaineauyl@gmail.com Received 30 September 2021; Revised 26 January 2022; Accepted 1 February 2022; Published 14 February 2022 Academic Editor: Claudio Pignata Copyright © 2022 Elaine Yuen Ling Au et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (e availability of next-generation sequencing (NGS) helps to resolve many of the diagnostic odysseys. Common variable immunodeficiency disease (CVID) is an entity encompassing a heterogenous group of conditions with hypogammaglobulinemia, and it is a diagnosis of exclusion. In recent years, with the advances of molecular diagnostics, more and more patients have been reclassified with more defined entities after their genetic causes were found. Here, we reported a young man, who was managed as CVID since childhood, presenting with recurrent infection, hypogammaglobulinemia, and immune thrombocytopenia (ITP). Finally, more than a decade after initial presentation, gene panel testing revealed a novel mutation in the MAGT1 gene. Collectively, the genetic findings and clinical presentations confirm the diagnosis of X-linked immunodeficiency with magnesium defect and Epstein–Barr virus infection and neoplasia (XMEN). MAGT1 is an evolutionarily conserved, magnesium-specific transporter expressed in all mammalian cells that plays an essential role in magnesium homeostasis. MAGT1 also acts as an accessory protein for STT3B, as catalytic subunits of the oligosaccharyltransferase protein complex, which carries out glycan chain transfer to proteins in the endoplasmic reticulum during N-glycosylation. Glycans play an essential role in the stability, mat- uration, and localization in glycoproteins that are important in our immune cells’ function. Mutation of the gene resulted in a rare X-linked recessive condition XMEN. (e disease has complete penetrance but variable expressivity. It is mainly associated with immunodeficiency, immunodysregulation, and predisposition to EBV-associated lymphoproliferation. Extraimmune manifes- tations have also been reported in some patient cohorts, including hepatic and neurological abnormalities. Overall, the pre- sentation varies among patients and overlaps with other clinical entities, in which diagnosis is challenging. Before the era of NGS, traditional workup hinges heavily on phenotype studies, followed by single-gene sequencing. (e diagnostic yield is low, and a significant delay in diagnosis is common. (is case illustrated the importance of early consideration of molecular studies in complex immunological cases without obvious secondary causes as an integral part of patient management. Epstein–Barr virus (EBV) infection and neoplasia (XMEN) [1]. 1. Introduction It has been reported in the literature [2, 3], but the clinical (e magnesium transporter 1 (MAGT1) gene is located in presentation of XMEN is variable and may overlap with other chromosome Xq21.1 and has 10 exons with the predominant clinical entities such as common variable immunodeficiency form encoding a 335-amino acid protein. MAGT1 is evolu- (CVID), and therefore, diagnosis is still challenging. Here, we tionarily conserved and ubiquitously expressed. Mutations of report the first case of Chinese XMEN in Hong Kong, with a novel mutation in the MAGT1 gene, who was previously di- the MAGT1 gene result in a rare X-linked recessive condition called X-linked immunodeficiency with magnesium defect and agnosed as CVID since childhood. 2 Case Reports in Immunology NK Cells CD8+ T Cells 89.9% 84.9% Control 3.7% 1.3% Patient 78.1% 90.8% Patient’s Mother NKG2D expression Figure 1: NKG2D expression in NK cells and CD8+ cytotoxic T cells. switched memory B cells and class-switched plasmablasts. 2. Case Vignette Despite a borderline low CD4 count, lymphocyte prolifer- A 25-year-old Chinese male student, with a prior diagnosis ation by mitogen stimulation was grossly unremarkable of CVID since childhood, was referred to the adult Im- (Supplementary Table S1). munology Clinic for continuation of care. He initially During subsequent follow-up, there was a progressive presented at 5 years old with recurrent chest infections and drop in IgG levels to around 500 mg/dl, with recurrent chest an episode of herpes zoster. Initial workup revealed an infections despite on azithromycin prophylaxis. (e patient immunoglobulin (Ig) G level of around 500–600 mg/dl, low was finally resumed on regular IVIg replacement at age 25. IgA, and absent antibody response following a pneumo- To elucidate the potential genetic causes, a targeted next- coccal vaccination challenge. He was diagnosed and man- generation sequencing (NGS) analysis was performed with aged as CVID with regular IVIg replacement. Illumina TruSight One Sequencing Panel. Analyses revealed (ree years following his initial presentation, he was also the patient was hemizygous for a novel pathogenic mutation diagnosed with immune thrombocytopenic purpura (ITP). in the MAGT1 gene (c.916del) and was confirmed by Sanger He was treated with courses of high-dose systemic steroid sequencing (Supplementary Figure S1). (e mutation leads and immunomodulatory doses of IVIg and remained well to frame shift starting at codon 306, changing leucine to thereafter. However, he stopped regular IVIg replacement at cysteine, and ends in a premature termination stop codon at age 11 as requested by his parents. 8 position downstream that is expected to disrupt the gene At age 24, he was admitted for an episode of ITP relapse function. (e variant is rare and is not found in population with the lowest platelet count down to 1 × 10^9/L and was databases such as gnomAD at the time of reporting. refractory to IVIg and pulse steroid therapy. He finally In view of the molecular results, NKG2D expression in responded to a course of anti-CD20 therapy (rituximab) and the patient’s NK cells and CD8+ cytotoxic Tcells was studied eltrombopag. Prior to the administration of anti-CD20 that was absent (Figure 1). EBV VCA antibodies and DNA therapy, his lymphocyte subset showed high B-cell counts measurement were unremarkable. His family history was (728/uL), with borderline low CD4 (around 400/uL). Fur- unrevealing, but his mother was a confirmed carrier after ther B-cells’ immunophenotyping revealed reduced genetic testing. Counts Case Reports in Immunology 3 Collectively, the variant was classified as pathogenic, and diagnosis remains challenging. Early consideration of the the findings confirmed the diagnosis of XMEN. NGS workup may help to resolve these diagnostic odysseys. Conflicts of Interest 3. Discussion (e authors declare that there are no conflicts of interest. We report a novel MAGT1 mutation found in the first Chinese XMEN patient in Hong Kong. MAGT1 is an evo- 2+ Supplementary Materials lutionarily conserved Mg -specific transporter expressed in all mammalian cells that is essential in magnesium ho- Supplementary Table S1: summary of laboratory results of 2+ meostasis. Chronic reductions in basal levels of free Mg our patient. Supplementary Figure S1: family pedigree and may contribute to the loss of NKG2D expression which is DNA sequencing chromatograms of the patient and his essential for antiviral and antitumor responses. In addition, parents. Supplementary Figure S2: X-inactivation analysis of MAGT1 also acts as an accessory protein for STT3B, as the patient’s mother (MAGT1 carrier). (Supplementary catalytic subunits of the oligosaccharyltransferase protein Materials) complex, which carries out glycan chain transfer to proteins in the endoplasmic reticulum during N-glycosylation. Im- References mune cells, in contrast to other tissues, rely exclusively on MAGT1 to facilitate asparagine (N)-linked glycosylation of [1] F.-Y. Li, B. Chaigne-Delalande, H. Su, G. Uzel, H. Matthews, specific STT3B-dependent glycoprotein that probably ex- and M. J. Lenardo, “XMEN disease: a new primary immu- 2+ plains the predominant immunological aberrant manifes- nodeficiency affecting Mg regulation of immunity against Epstein-Barr virus,” Blood, vol. 123, no. 14, pp. 2148–2152, tations of the disease [2, 4, 5]. Our patient demonstrated a decreased expression of [2] J. C. Ravell, S. D. Chauvin, T. He, and M. Lenardo, “An update NKG2D in his NK cells and cytotoxic Tcells. He also had low on XMEN disease,” Journal of Clinical Immunology, vol. 40, serum immunoglobulins, along with impaired response to no. 5, pp. 671–681, 2020. polysaccharide antigens, as reported in the literature [4]. [3] X. Huang, D. Liu, Z. Gao, and C. Liu, “Case report: EBV- (ough he showed elevated B-cell counts, the class-switched positive extra-nodal marginal zone lymphoma associated with memory B cells and plasmablasts were low. (e underlying XMEN disease caused by a novel hemizygous mutation in pathogenesis affecting the B-cell compartment in XMEN has MAGT1,” Frontiers in Oncology, vol. 11, Article ID 653266, not been fully elucidated yet, though the previous mouse model study showed abolished MAGT1 function caused [4] J. C. Ravell, M. Matsuda-Lennikov, S. D. Chauvin et al., “Defective glycosylation and multisystem abnormalities imbalanced cation homeostasis and an impact on B-cell characterize the primary immunodeficiency XMEN disease,” development [6]. "e Journal of Clinical Investigation, vol. 130, no. 1, pp. 507– In the absence of a positive family history, physicians 522, 2020. may not be aware of this entity, and diagnosis may be [5] E. Blommaert, R. Peanne, ´ N. A. Cherepanova et al., “Mutations delayed until complications arise. In contrast with the in MAGT1 lead to a glycosylation disorder with a variable conventional single gene-by-gene workup which heavily phenotype,” Proceedings of the National Academy of Sciences, relies on the characteristic phenotype, NGS serves as a vol. 116, no. 20, pp. 9865–9870, 2019. powerful tool to assay gene panels or even exome/genome [6] S. K. Gotru, J. Gil-Pulido, N. Beyersdorf et al., “Cutting edge: within a single assay that hastens the workup with enhanced imbalanced cation homeostasis in MAGT1-deficient B cells yield. Knowing the underlying genetic cause has significant dysregulates B cell development and signaling in mice,” "e Journal of Immunology, vol. 200, no. 8, pp. 2529–2534, 2018. implications on prognostication and management, such as [7] F.-Y. Li, B. Chaigne-Delalande, C. Kanellopoulou et al., close surveillance of EBV-related complications and 2+ “Second messenger role for Mg revealed by human T-cell malignancies. immunodeficiency,” Nature, vol. 475, no. 7357, pp. 471–476, Workup for other family members is also important in hereditary conditions. Interestingly, the mother had normal [8] D. Dimitrova, J. J. Rose, G. Uzel et al., “Successful bone marrow NKG2D expression despite being a carrier. In fact, our transplantation for XMEN: hemorrhagic risk uncovered,” lyonization study confirmed a pattern of X chromosome Journal of Clinical Immunology, vol. 39, no. 1, pp. 1–3, 2019. inactivation skewed towards the normal allele (Supple- [9] E. M. Klinken, P. E. Gray, B. Pillay et al., “Diversity of XMEN mentary Figure S2), as similarly reported in previous studies disease: description of 2 novel variants and analysis of [7–9]. (erefore, although NKG2D expression serves as a the lymphocyte phenotype,” Journal of Clinical Immunology, classical biomarker for XMEN, genetic studies are required vol. 40, no. 2, pp. 299–309, 2020. for carrier detection. 4. Conclusion In summary, we report a case of XMEN, with a novel mutation in the MAGT1 gene. (e condition is rare, with variable clinical phenotype. While reports of further cases may help us to better delineate the phenotype spectrum, http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

Novel MAGT1 Mutation Found in the First Chinese XMEN in Hong Kong

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Copyright © 2022 Elaine Yuen Ling Au et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Case Reports in Immunology Volume 2022, Article ID 2390167, 3 pages https://doi.org/10.1155/2022/2390167 Case Report Novel MAGT1 Mutation Found in the First Chinese XMEN in Hong Kong 1 1 1 2 Elaine Yuen Ling Au , Edmund Kwok Kwan Tung, Ricky Wai Ki Ip, and Philip Hei Li Department of Pathology, Queen Mary Hospital, Pok Fu Lam, Hong Kong Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, "e University of Hong Kong, Pok Fu Lam, Hong Kong Correspondence should be addressed to Elaine Yuen Ling Au; elaineauyl@gmail.com Received 30 September 2021; Revised 26 January 2022; Accepted 1 February 2022; Published 14 February 2022 Academic Editor: Claudio Pignata Copyright © 2022 Elaine Yuen Ling Au et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (e availability of next-generation sequencing (NGS) helps to resolve many of the diagnostic odysseys. Common variable immunodeficiency disease (CVID) is an entity encompassing a heterogenous group of conditions with hypogammaglobulinemia, and it is a diagnosis of exclusion. In recent years, with the advances of molecular diagnostics, more and more patients have been reclassified with more defined entities after their genetic causes were found. Here, we reported a young man, who was managed as CVID since childhood, presenting with recurrent infection, hypogammaglobulinemia, and immune thrombocytopenia (ITP). Finally, more than a decade after initial presentation, gene panel testing revealed a novel mutation in the MAGT1 gene. Collectively, the genetic findings and clinical presentations confirm the diagnosis of X-linked immunodeficiency with magnesium defect and Epstein–Barr virus infection and neoplasia (XMEN). MAGT1 is an evolutionarily conserved, magnesium-specific transporter expressed in all mammalian cells that plays an essential role in magnesium homeostasis. MAGT1 also acts as an accessory protein for STT3B, as catalytic subunits of the oligosaccharyltransferase protein complex, which carries out glycan chain transfer to proteins in the endoplasmic reticulum during N-glycosylation. Glycans play an essential role in the stability, mat- uration, and localization in glycoproteins that are important in our immune cells’ function. Mutation of the gene resulted in a rare X-linked recessive condition XMEN. (e disease has complete penetrance but variable expressivity. It is mainly associated with immunodeficiency, immunodysregulation, and predisposition to EBV-associated lymphoproliferation. Extraimmune manifes- tations have also been reported in some patient cohorts, including hepatic and neurological abnormalities. Overall, the pre- sentation varies among patients and overlaps with other clinical entities, in which diagnosis is challenging. Before the era of NGS, traditional workup hinges heavily on phenotype studies, followed by single-gene sequencing. (e diagnostic yield is low, and a significant delay in diagnosis is common. (is case illustrated the importance of early consideration of molecular studies in complex immunological cases without obvious secondary causes as an integral part of patient management. Epstein–Barr virus (EBV) infection and neoplasia (XMEN) [1]. 1. Introduction It has been reported in the literature [2, 3], but the clinical (e magnesium transporter 1 (MAGT1) gene is located in presentation of XMEN is variable and may overlap with other chromosome Xq21.1 and has 10 exons with the predominant clinical entities such as common variable immunodeficiency form encoding a 335-amino acid protein. MAGT1 is evolu- (CVID), and therefore, diagnosis is still challenging. Here, we tionarily conserved and ubiquitously expressed. Mutations of report the first case of Chinese XMEN in Hong Kong, with a novel mutation in the MAGT1 gene, who was previously di- the MAGT1 gene result in a rare X-linked recessive condition called X-linked immunodeficiency with magnesium defect and agnosed as CVID since childhood. 2 Case Reports in Immunology NK Cells CD8+ T Cells 89.9% 84.9% Control 3.7% 1.3% Patient 78.1% 90.8% Patient’s Mother NKG2D expression Figure 1: NKG2D expression in NK cells and CD8+ cytotoxic T cells. switched memory B cells and class-switched plasmablasts. 2. Case Vignette Despite a borderline low CD4 count, lymphocyte prolifer- A 25-year-old Chinese male student, with a prior diagnosis ation by mitogen stimulation was grossly unremarkable of CVID since childhood, was referred to the adult Im- (Supplementary Table S1). munology Clinic for continuation of care. He initially During subsequent follow-up, there was a progressive presented at 5 years old with recurrent chest infections and drop in IgG levels to around 500 mg/dl, with recurrent chest an episode of herpes zoster. Initial workup revealed an infections despite on azithromycin prophylaxis. (e patient immunoglobulin (Ig) G level of around 500–600 mg/dl, low was finally resumed on regular IVIg replacement at age 25. IgA, and absent antibody response following a pneumo- To elucidate the potential genetic causes, a targeted next- coccal vaccination challenge. He was diagnosed and man- generation sequencing (NGS) analysis was performed with aged as CVID with regular IVIg replacement. Illumina TruSight One Sequencing Panel. Analyses revealed (ree years following his initial presentation, he was also the patient was hemizygous for a novel pathogenic mutation diagnosed with immune thrombocytopenic purpura (ITP). in the MAGT1 gene (c.916del) and was confirmed by Sanger He was treated with courses of high-dose systemic steroid sequencing (Supplementary Figure S1). (e mutation leads and immunomodulatory doses of IVIg and remained well to frame shift starting at codon 306, changing leucine to thereafter. However, he stopped regular IVIg replacement at cysteine, and ends in a premature termination stop codon at age 11 as requested by his parents. 8 position downstream that is expected to disrupt the gene At age 24, he was admitted for an episode of ITP relapse function. (e variant is rare and is not found in population with the lowest platelet count down to 1 × 10^9/L and was databases such as gnomAD at the time of reporting. refractory to IVIg and pulse steroid therapy. He finally In view of the molecular results, NKG2D expression in responded to a course of anti-CD20 therapy (rituximab) and the patient’s NK cells and CD8+ cytotoxic Tcells was studied eltrombopag. Prior to the administration of anti-CD20 that was absent (Figure 1). EBV VCA antibodies and DNA therapy, his lymphocyte subset showed high B-cell counts measurement were unremarkable. His family history was (728/uL), with borderline low CD4 (around 400/uL). Fur- unrevealing, but his mother was a confirmed carrier after ther B-cells’ immunophenotyping revealed reduced genetic testing. Counts Case Reports in Immunology 3 Collectively, the variant was classified as pathogenic, and diagnosis remains challenging. Early consideration of the the findings confirmed the diagnosis of XMEN. NGS workup may help to resolve these diagnostic odysseys. Conflicts of Interest 3. Discussion (e authors declare that there are no conflicts of interest. We report a novel MAGT1 mutation found in the first Chinese XMEN patient in Hong Kong. MAGT1 is an evo- 2+ Supplementary Materials lutionarily conserved Mg -specific transporter expressed in all mammalian cells that is essential in magnesium ho- Supplementary Table S1: summary of laboratory results of 2+ meostasis. Chronic reductions in basal levels of free Mg our patient. Supplementary Figure S1: family pedigree and may contribute to the loss of NKG2D expression which is DNA sequencing chromatograms of the patient and his essential for antiviral and antitumor responses. In addition, parents. Supplementary Figure S2: X-inactivation analysis of MAGT1 also acts as an accessory protein for STT3B, as the patient’s mother (MAGT1 carrier). (Supplementary catalytic subunits of the oligosaccharyltransferase protein Materials) complex, which carries out glycan chain transfer to proteins in the endoplasmic reticulum during N-glycosylation. Im- References mune cells, in contrast to other tissues, rely exclusively on MAGT1 to facilitate asparagine (N)-linked glycosylation of [1] F.-Y. Li, B. Chaigne-Delalande, H. Su, G. Uzel, H. Matthews, specific STT3B-dependent glycoprotein that probably ex- and M. J. Lenardo, “XMEN disease: a new primary immu- 2+ plains the predominant immunological aberrant manifes- nodeficiency affecting Mg regulation of immunity against Epstein-Barr virus,” Blood, vol. 123, no. 14, pp. 2148–2152, tations of the disease [2, 4, 5]. Our patient demonstrated a decreased expression of [2] J. C. Ravell, S. D. Chauvin, T. He, and M. Lenardo, “An update NKG2D in his NK cells and cytotoxic Tcells. He also had low on XMEN disease,” Journal of Clinical Immunology, vol. 40, serum immunoglobulins, along with impaired response to no. 5, pp. 671–681, 2020. polysaccharide antigens, as reported in the literature [4]. [3] X. Huang, D. Liu, Z. Gao, and C. Liu, “Case report: EBV- (ough he showed elevated B-cell counts, the class-switched positive extra-nodal marginal zone lymphoma associated with memory B cells and plasmablasts were low. (e underlying XMEN disease caused by a novel hemizygous mutation in pathogenesis affecting the B-cell compartment in XMEN has MAGT1,” Frontiers in Oncology, vol. 11, Article ID 653266, not been fully elucidated yet, though the previous mouse model study showed abolished MAGT1 function caused [4] J. C. Ravell, M. Matsuda-Lennikov, S. D. Chauvin et al., “Defective glycosylation and multisystem abnormalities imbalanced cation homeostasis and an impact on B-cell characterize the primary immunodeficiency XMEN disease,” development [6]. "e Journal of Clinical Investigation, vol. 130, no. 1, pp. 507– In the absence of a positive family history, physicians 522, 2020. may not be aware of this entity, and diagnosis may be [5] E. Blommaert, R. Peanne, ´ N. A. Cherepanova et al., “Mutations delayed until complications arise. In contrast with the in MAGT1 lead to a glycosylation disorder with a variable conventional single gene-by-gene workup which heavily phenotype,” Proceedings of the National Academy of Sciences, relies on the characteristic phenotype, NGS serves as a vol. 116, no. 20, pp. 9865–9870, 2019. powerful tool to assay gene panels or even exome/genome [6] S. K. Gotru, J. Gil-Pulido, N. Beyersdorf et al., “Cutting edge: within a single assay that hastens the workup with enhanced imbalanced cation homeostasis in MAGT1-deficient B cells yield. Knowing the underlying genetic cause has significant dysregulates B cell development and signaling in mice,” "e Journal of Immunology, vol. 200, no. 8, pp. 2529–2534, 2018. implications on prognostication and management, such as [7] F.-Y. Li, B. Chaigne-Delalande, C. Kanellopoulou et al., close surveillance of EBV-related complications and 2+ “Second messenger role for Mg revealed by human T-cell malignancies. immunodeficiency,” Nature, vol. 475, no. 7357, pp. 471–476, Workup for other family members is also important in hereditary conditions. Interestingly, the mother had normal [8] D. Dimitrova, J. J. Rose, G. Uzel et al., “Successful bone marrow NKG2D expression despite being a carrier. In fact, our transplantation for XMEN: hemorrhagic risk uncovered,” lyonization study confirmed a pattern of X chromosome Journal of Clinical Immunology, vol. 39, no. 1, pp. 1–3, 2019. inactivation skewed towards the normal allele (Supple- [9] E. M. Klinken, P. E. Gray, B. Pillay et al., “Diversity of XMEN mentary Figure S2), as similarly reported in previous studies disease: description of 2 novel variants and analysis of [7–9]. (erefore, although NKG2D expression serves as a the lymphocyte phenotype,” Journal of Clinical Immunology, classical biomarker for XMEN, genetic studies are required vol. 40, no. 2, pp. 299–309, 2020. for carrier detection. 4. Conclusion In summary, we report a case of XMEN, with a novel mutation in the MAGT1 gene. (e condition is rare, with variable clinical phenotype. While reports of further cases may help us to better delineate the phenotype spectrum,

Journal

Case Reports in ImmunologyHindawi Publishing Corporation

Published: Feb 14, 2022

References