Abstract
In the diagnosis of primary immunodeficiencies which are heterogeneous groups of genetic disorders, next-generation sequencing strategies take an important place. Protein expression analyses and some functional studies which are fundamental to determine the pathogenicity of the mutation are also performed to accelerate the diagnosis of PIDs before sequencing. However, protein expressions and functions do not always reflect the genetic and clinical background of the disease even the existence of a pathogenic variant or vice versa. In this study, it was aimed to understand genotype-proteophenotype-clinicophenotype correlation by investigating the effect of mutation types on protein expression, function, and clinical severity in X-linked, autosomal dominant, and autosomal recessive forms of PIDs. It was searched in PubMed and Web of Science without any restrictions on study design and publication time. Totally, 1178 patients with PIDs who have 553 different mutations were investigated from 174 eligible full-text articles. For all mutations, the effect of mutation type on protein expressions and protein functions was analyzed. Furthermore, the most frequent missense and nonsense mutations that were identified in patients with PIDs were evaluated to determine the genotype-clinicophenotype correlation. Protein expressions and functions were changed depending on the mutation type and the affected domain. A significant relationship was observed between protein expression level and clinical severity among all investigated patients. There was also a positive correlation between clinical severity and the affected domains. Mutation types and affected domains should be carefully evaluated with respect to protein expression levels and functional changes during the evaluation of clinico-phenotype.
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Arjunaraja S, Snow AL. Gain-of-function mutations and immunodeficiency: at a loss for proper tuning of lymphocyte signaling. Curr Opin Allergy Clin Immunol. Published online 2015. https://doi.org/10.1097/ACI.0000000000000217.
Jhamnani RD, Rosenzweig SD. An update on gain-of-function mutations in primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. Published online 2017. https://doi.org/10.1097/ACI.0000000000000401.
Bousfiha A, Jeddane L, Picard C, et al. Human ınborn errors of ımmunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol. 2020;40(1):24–64. https://doi.org/10.1007/s10875-019-00737-x.
Harvey L, Arnold B, S Lawrence Z, Pau l M, David B, James D. Molecular cell biology. 4th Edition. 2000.
Griffiths AJF, Gelbart WM, Miller JH, et al. Modern genetic analysis: protein function and malfunction in cells. New York: W. H. Freeman; 1999.
Shendure J, Balasubramanian S, Church GM, et al. DNA sequencing at 40: past, present, and future. Nature. 2017;550:345–53. https://doi.org/10.1038/nature24286.
Salzer U, Sack U, Fuchs I. Flow cytometry in the diagnosis and follow up of human primary immunodeficiencies. Electron J Int Fed Clin Chem Lab Med. Published online 2019.
Madkaikar MR, Shabrish S, Kulkarni M, et al. Application of flow cytometry in primary immunodeficiencies: experience from India. Front Immunol. Published online 2019. https://doi.org/10.3389/fimmu.2019.01248.
Somech R, Roifman CM. Mutation analysis should be performed to rule out γC deficiency in children with functional severe combined immune deficiency despite apparently normal immunologic tests. J Pediatr. 2005;147(4):555–7. https://doi.org/10.1016/j.jpeds.2005.05.010.
Illig D, Navratil M, Kelečić J, et al. Alternative splicing rescues loss of common gamma chain function and results in IL-21R-like deficiency. J Clin Immunol. 2019;39(2):207–15. https://doi.org/10.1007/s10875-019-00606-7.
Kiani-Alikhan S, Yong PFK, Gilmour KC, Grosse-Kreul D, Davies EG, Ibrahim MAA. Phenotypic heterogeneity in a family with a CD40 ligand intracellular domain mutation. J Clin Immunol. 2012;32(1):70–7. https://doi.org/10.1007/s10875-011-9607-6.
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. Published online 2009. https://doi.org/10.1136/bmj.b2700.
den Dunnen JT, Dalgleish R, Maglott DR, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. Published online 2016. https://doi.org/10.1002/humu.22981.
Grimbacher B, Schäffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. Published online 1999. https://doi.org/10.1086/302547
Casanova JL, Conley ME, Seligman SJ, Abel L, Notarangelo LD. Guidelines for genetic studies in single patients: Lessons from primary immunodeficiencies. J Exp Med. Published online 2014. https://doi.org/10.1084/jem.20140520
Kanegane H, Hoshino A, Okano T, et al. Flow cytometry-based diagnosis of primary immunodeficiency diseases. Allergol Int. 2018;67(1):43–54. https://doi.org/10.1016/j.alit.2017.06.003.
Oskay Halaclı S, Cagdas D, Tezcan I. Flow cytometry is a reliable tool in the diagnosis of STK4 deficiency. Asthma Allergy Immunol. Published online 2020.https://doi.org/10.21911/aai.518
Essadssi S, Krami AM, Elkhattabi L, et al. Computational analysis of nsSNPs of ADA gene in severe combined ımmunodeficiency using molecular modeling and dynamics simulation. J Immunol Res. Published online 2019. https://doi.org/10.1155/2019/5902391
López-Mejías R, Del Pozo N, Fernández-Arquero M, et al. Role of polymorphisms in the TNFRSF13B (TACI) gene in Spanish patients with immunoglobulin A deficiency. Tissue Antigens. Published online 2009. https://doi.org/10.1111/j.1399-0039.2009.01253.x
Neves JF, Martins C, Cordeiro AI, et al. Novel IL2RG Mutation Causes Leaky T LOW B + NK + SCID with nodular regenerative hyperplasia and normal IL-15 STAT5 Phosphorylation. J Pediatr Hematol Oncol. 2019;41(4):328–33. https://doi.org/10.1097/MPH.0000000000001232.
Katta A, Hong J, Knutsen AP. Hyper immunoglobulin M syndrome in a 15-year-old boy caused by a Gly219Arg missense mutation. Ann Allergy, Asthma Immunol. 2013;110(5):391–3. https://doi.org/10.1016/j.anai.2013.02.011.
De Vries E, Noordzij JG, Davies EG, et al. The 782C → T (T254M) XHIM mutation: lack of a tight phenotype-genotype relationship [8] (multiple letters). Blood. 1999;94(4):1488–90. https://doi.org/10.1182/blood.v94.4.1488.
Seyama K, Nonoyama S, Gangsaas I, et al. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood. 1998;92(7):2421–34. https://doi.org/10.1182/blood.v92.7.2421.
Mella P, Imberti L, Brugnoni D, et al. Development of autologous T lymphocytes in two males with X-linked severe combined immune deficiency: molecular and cellular characterization. Clin Immunol. 2000;95(1):39–50. https://doi.org/10.1006/clim.2000.4842.
Imai K, Shimadzu M, Kubota T, et al. Female hyper IgM syndrome type 1 with a chromosomal translocation disrupting CD40LG. Biochim Biophys Acta - Mol Basis Dis. 2006;1762(3):335–40. https://doi.org/10.1016/j.bbadis.2005.10.003.
Schumacher RF, Mella P, Badolato R, et al. Complete genomic organization of the human JAK3 gene and mutation analysis in severe combined immunodeficiency by single-strand conformation polymorphism. Hum Genet. 2000;106(1):73–9. https://doi.org/10.1007/s004390051012.
Frucht DM, Gadina M, Jagadeesh GJ, et al. Unexpected and variable phenotypes in a family with JAK3 deficiency. Genes Immun. 2001;2(8):422–32. https://doi.org/10.1038/sj.gene.6363802.
Buchbinder D, Kirov I, Danielson J, et al. Compound heterozygous DOCK8 mutations in a patient with B lymphoblastic leukemia and EBV-associated diffuse large B cell lymphoma. J Clin Immunol. Published online 2019. https://doi.org/10.1007/s10875-019-00663-y
Stepensky P, Keller B, Shamriz O, et al. Deep intronic mis-splicing mutation in JAK3 gene underlies T-B+NK- severe combined immunodeficiency phenotype. Clin Immunol. 2016;163:91–5. https://doi.org/10.1016/j.clim.2016.01.001.
Hsu AP, Pittaluga S, Martinez B, et al. IL2RG reversion event in a common lymphoid progenitor leads to delayed diagnosis and milder phenotype. J Clin Immunol. 2015;35(5):449–53. https://doi.org/10.1007/s10875-015-0174-0.
De Saint BG, Tabone MD, Durandy A, Phan F, Fischer A, Le Deist F. CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization. Eur J Immunol. 1999;29(1):367–73. https://doi.org/10.1002/(SICI)1521-4141(199901)29:01%3c367::AID-IMMU367%3e3.0.CO;2-4.
Danielian S, Oleastro M, Eva Rivas M, Cantisano C, Zelazko M. Clinical follow-up of 11 Argentinian CD40L-deficient patients with 7 unique mutations including the so-called “milder” mutants. J Clin Immunol. Published online 2007. https://doi.org/10.1007/s10875-007-9089-8
Phan ANL, Pham TTT, Huynh N, et al. Novel compound heterozygous stop-gain mutations of LRBA in a Vietnamese patient with common variable ımmune deficiency. Mol Genet Genomic Med. Published online 2020. https://doi.org/10.1002/mgg3.1216
Gilmour KC, Walshe D, Heath S, et al. Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM. J Clin Pathol - Mol Pathol. 2003;56(5):256–62. https://doi.org/10.1136/mp.56.5.256.
Seyama K, Osborne WRA, Ochs HD. CD40 ligand mutants responsible for X-linked hyper-IgM syndrome associate with wild type CD40 ligand. J Biol Chem. 1999;274(16):11310–20. https://doi.org/10.1074/jbc.274.16.11310.
Acknowledgements
The author would like to thank Prof. Ilhan Tezcan, MD, PhD, and Prof. Deniz Cagdas Ayvaz, MD, PhD, for their precious supports. I also thank Dr. Burcin Halacli for his sincere help in some correlation analyses.
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Flowchart of the systematic search and selection process. (DOCX 92 KB)
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Halacli, S.O. The effect of mutatio-type on proteo-phenotype and clinico-phenotype in selected primary immunodeficiencies. Immunol Res 70, 56–66 (2022). https://doi.org/10.1007/s12026-021-09239-8
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DOI: https://doi.org/10.1007/s12026-021-09239-8