Abstract
The X-linked hyper-IgM syndrome (X-HIGM1) is a rare primary immunodeficiency disorder (PID) caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). X-HIGM1 is characterized by normal or elevated serum levels of IgM in association with decreased levels of IgG, IgA, and IgE. The CD40LG protein expressed on activated T cells interacts with its receptor protein, CD40, on B lymphocytes and dendritic cells. Mutations in the CD40LG gene lead to the production of an abnormal CD40L protein that fails to attach to its receptor, CD40 on B cells resulting in failure to produce IgG, IgA, and IgE antibodies. In the present study, we investigated the molecular defects underlying such a PID in a patient presenting with clinical history of pneumonia and acute respiratory distress syndrome (ARDS) at 7 months of age and diagnosed as transient hypogammaglobulinemia with decreased levels of IgG and increased levels of IgM. We have identified a novel and yet to be reported frame shift deletion of a single base pair (c.229delA) in exon 2 (p.Arg77AspfsTer6) of the CD40L gene ensuing the premature truncation of the protein by 6 amino acids by targeted gene sequencing. This frame shift mutation identified as a CD40L variant was found to be pathogenic which was also validated by Sanger sequencing. The in-silico analysis of c.229 del A mutation also predicted the change to be pathological affecting the structure and function of the CD40L (CD40L, CD154) protein and its protein–protein interaction properties.
Abbreviations
- ARDS:
-
Acute respiratory distress syndrome
- CD40L:
-
CD40 ligand
- CSR:
-
Class switch recombination
- Ig:
-
Immunoglobulin
- HIGM:
-
Hyper-IgM syndrome
- PID:
-
Primary immunodeficiency disorder
- SHM:
-
Somatic hypermutation
- TNF:
-
Tumor necrosis factor
- THFH:
-
Tumor necrosis factor homology
- X-HIGM1:
-
X-linked hyper-IgM syndrome
References
Bajorath J, Chalupny NJ, Marken JS, Siadak AW, Skonier J, Gordon M, Hollenbaugh D, Noelle RJ et al (1995) Identification of residues on CD40 and its ligand which are critical for the receptor-ligand interaction. Biochem 34:1833–44
Etzioni A (2004) Ochs HD 2004 The hyper IgM syndrome—an evolving story. Pediatr Res 56:519–525
Gilmour KC, Walshe D, Heath S, Monaghan G, Loughlin S, Lester T, Norbury G, Cale CM (2003) Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM. Mol Pathol 56:256
Jesus AA, Duarte AJ, Oliveira JB (2008) Autoimmunity in hyper-IgM syndrome. J Clin Immunol 28:62–66
Karpusas M, Hsu YM, Wang JH, Thompson J, Lederman S, Chess L, Thomas D (1995) 2 Å crystal structure of an extracellular fragment of human CD40 ligand. Structure 3:1031–9
Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, Resnick I, Fasth A et al (1997) Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 131:47–54
Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A (1992) A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci 89:6550–6554
Notarangelo LD, Hayward AR (2000) X-linked immunodeficiency with hyper-IgM (XHIM). Clin Exp Immunol 120:399–405
Qamar N, Fuleihan RL (2014) The hyper IgM syndromes. Clin Rev Allergy Immunol 46:120–130
Sarode AY, Jha MK, Zutshi S, Ghosh SK, Mahor H, Sarma U, Saha B (2020) residue-specific message encoding in CD40-ligand. iScience 23:101441
van Kooten C, Banchereau J (2000) CD40-CD40 ligand. J Leukoc Biol 67:2–17
Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME (2003) The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine 82:373–84
Yamniuk AP, Suri A, Krystek SR, Tamura J, Ramamurthy V, Kuhn R, Carroll K, Fleener C et al (2016) Functional antagonism of human CD40 achieved by targeting a unique species-specific epitope. J Mol Biol 428:2860–2879
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We thank the patient and his family for their contribution to the study.
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R.R performed the sequencing experiments, Y.K. was responsible for the diagnosis and identifying the patient and providing the patient and his family’s blood samples for the study, P.S. did the complete in silico and bioinformatics analysis for the study, and A.K. supervised the in silico and bioinformatics part of the study. A.M conceptualized, designed the experiments, and wrote the complete manuscript.
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Ramachandran, R., Krishnan, Y., Singh, P. et al. X-linked hyper-immunoglobulin M syndrome harboring a novel CD40-ligand gene mutation: a case report. Immunogenetics 75, 191–194 (2023). https://doi.org/10.1007/s00251-022-01289-y
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DOI: https://doi.org/10.1007/s00251-022-01289-y