Gene hunt

  • Research Project

Gene hunt

Identification of monogenetic defects in patients with immunodeficiency and/or immune dysregulation

During my postdoctoral time at the NIH in Bethesda, Maryland, I learned under the guidance of my mentor Jennifer Puck how to positionally clone candidate genes for Mendelian human diseases. Coming back to Freiburg as a young physician-scientist, I used my knowledge to identify the first monogenic cause (ICOS deficiency; Nat Immunol, 2003) for a condition known as CVID, which is the commonest symptomatic primary immunodeficiency in men. To date, CVID is known to be caused by at least 70 different monogenic causes, of which I contributed about 12 of them. I also identified the first monogenic cause for inflammatory bowel disease (IL10- and IL10-receptor deficiency; NEJM, 2009), and the first cause of monogenic susceptibility to fungal disease (CARD9 deficiency; NEJM, 2009). I also helped to identify the genetic cause for Kostmann’s disease (HAX1 deficiency; Nat Genet, 2007). More recently, I discovered that monogenic mutation in CTLA4 (Nat. Med. 2014) lead to a multi-organ immune dysregulation including immunodeficiency, and that mutations in NFKB1 (AJHG, 2015) or NFKB2 (Front Immunol, 2019) may also lead to severe immune dysregulation. In this tradition, we continue to contribute to the ever-growing list of monogenic causes for inborn errors of immunity, which currently (2024) encompasses almost 500 disease genes.

References

  1. Rolles B, et al. Telomere biology disorders may manifest as common variable immunodeficiency (CVID). Clin Immunol. 2023;257:109837. doi: 10.1016/j.clim.2023.109837.
  2. Peng XP, et al. Next generation sequencing (NGS)-based approach to diagnosing Algerian patients with suspected inborn errors of immunity (IEIs). Clin Immunol. 2023;256:109758. doi: 10.1016/j.clim.2023.109758.
  3. Fliegauf M, et al. Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50. Front Immunol. 2022;13:965326. doi: 10.3389/fimmu.2022.965326.
  4. Rojas-Restrepo J, et al. Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study. Front Immunol. 2021;12:786516. doi: 10.3389/fimmu.2021.786516.
  5. Frede N, et al. Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis. J Clin Immunol. 2021;41(8):1804-38. doi: 10.1007/s10875-021-01086-4.
  6. Fliegauf M, et al. A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage. Front Immunol. 2021;12:621503. doi: 10.3389/fimmu.2021.621503.
  7. Eskandarian Z, et al. Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency. Front Immunol. 2019;10:568. doi: 10.3389/fimmu.2019.00568.
  8. Klemann C, et al. Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2. Front Immunol. 2019;10:297. doi: 10.3389/fimmu.2019.00297.
  9. Frey-Jakobs S, et al. ZNF341 controls STAT3 expression and thereby immunocompetence. Sci Immunol. 2018;3(24) doi: 10.1126/sciimmunol.aat4941.
  10. Petersen BS, et al. Targeted Gene Panel Sequencing for Early-onset Inflammatory Bowel Disease and Chronic Diarrhea. Inflamm Bowel Dis. 2017;23(12):2109-20. doi: 10.1097/mib.0000000000001235.
  11. Schubert D, et al. Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1). J Allergy Clin Immunol. 2018;141(4):1427-38. doi: 10.1016/j.jaci.2017.06.042.
  12. Schepp J, et al. Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood. Arthritis Rheumatol. 2017;69(8):1689-700. doi: 10.1002/art.40147.
  13. Volk T, et al. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Hum Mol Genet. 2015;24(25):7361-72. doi: 10.1093/hmg/ddv437.
  14. Elgizouli M, et al. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency. Clin Exp Immunol. 2016;183(2):221-9. doi: 10.1111/cei.12706.
  15. Fliegauf M, et al. Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. Am J Hum Genet. 2015;97(3):389-403. doi: 10.1016/j.ajhg.2015.07.008.
  16. Dziadzio M, et al. Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency. J Clin Immunol. 2015;35(5):439-44. doi: 10.1007/s10875-015-0166-0.
  17. Schubert D, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410-6. doi: 10.1038/nm.3746.
  18. Sassi A, et al. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J Allergy Clin Immunol. 2014;133(5):1410-9, 9.e1-13. doi: 10.1016/j.jaci.2014.02.025.
  19. Lanternier F, et al. Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med. 2013;369(18):1704-14. doi: 10.1056/NEJMoa1208487.
  20. Lopez-Herrera G, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986-1001. doi: 10.1016/j.ajhg.2012.04.015.
  21. Glocker EO, et al. Infant colitis–it’s in the genes. Lancet. 2010;376(9748):1272. doi: 10.1016/s0140-6736(10)61008-2.
  22. Woellner C, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol. 2010;125(2):424-32.e8. doi: 10.1016/j.jaci.2009.10.059.
  23. Engelhardt KR, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. 2009;124(6):1289-302.e4. doi: 10.1016/j.jaci.2009.10.038.
  24. Glocker EO, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361(21):2033-45. doi: 10.1056/NEJMoa0907206.
  25. Glocker EO, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. 2009;361(18):1727-35. doi: 10.1056/NEJMoa0810719.
  26. Salzer U, et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2009;113(9):1967-76. doi: 10.1182/blood-2008-02-141937.
  27. Salzer U, et al. Sequence analysis of BIRC4/XIAP in male patients with common variable immunodeficiency. Int Arch Allergy Immunol. 2008;147(2):147-51. doi: 10.1159/000135702.
  28. Salzer U, et al. Screening of functional and positional candidate genes in families with common variable immunodeficiency. BMC Immunol. 2008;9:3. doi: 10.1186/1471-2172-9-3.
  29. Pfeifer D, et al. The hyper-IgE syndrome is not caused by a microdeletion syndrome. Immunogenetics. 2007;59(12):913-26. doi: 10.1007/s00251-007-0257-z.
  30. Holland SM, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608-19. doi: 10.1056/NEJMoa073687.
  31. Salzer U, et al. Sequence analysis of TNFRSF13b, encoding TACI, in patients with systemic lupus erythematosus. J Clin Immunol. 2007;27(4):372-7. doi: 10.1007/s10875-007-9094-y.
  32. Klein C, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86-92. doi: 10.1038/ng1940.
  33. Bohn G, et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med. 2007;13(1):38-45. doi: 10.1038/nm1528.
  34. Finck A, et al. Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. Eur J Hum Genet. 2006;14(7):867-75. doi: 10.1038/sj.ejhg.5201634.
  35. Jung J, et al. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood. 2006;108(1):362-9. doi: 10.1182/blood-2005-11-4377.
  36. Schäffer AA, et al. Analysis of families with common variable immunodeficiency (CVID) and IgA deficiency suggests linkage of CVID to chromosome 16q. Hum Genet. 2006;118(6):725-9. doi: 10.1007/s00439-005-0101-1.
  37. Salzer U, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37(8):820-8. doi: 10.1038/ng1600.
  38. Salzer U, et al. ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol. 2004;113(3):234-40. doi: 10.1016/j.clim.2004.07.002.
  39. Grimbacher B, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4(3):261-8. doi: 10.1038/ni902.

Funding

This project is funded by internal funds of the Medical Center – University of Freiburg.

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Prof. Dr. med. Bodo Grimbacher
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Prof. Dr. med. Bodo Grimbacher

MEDICAL CENTER – UNIVERSITY OF FREIBURG
Institute for Immunodeficiency (IFI)
Center for Chronic Immundeficiency (CCI)
Breisacher Str. 115
79106 Freiburg
Phone +49 (0)761 270-77732
E-Mail
www.uniklinik-freiburg.de/cci