A novel disease-causing CD40L mutation reduces expression of CD40 ligand, but preserves CD40 binding capacity.
Mutations in CD40 ligand (CD40L) that permit residual CD40L expression typically impair binding of CD40. We report a male patient who presented with recurrent bacterial respiratory tract infections, normal IgM, decreased IgG, absent IgA levels, and CD40L expression at ~50% of the level observed in the normal control. He subsequently developed autoimmunity, inflammatory bowel disease, severe opportunistic infections suggestive of a combined immunodeficiency, and a cervical spine schwannoma. Whole exome sequencing of the patient's genomic DNA revealed a novel missense mutation (p.H47Y) in CD40L. Although this mutation was predicted to be benign in silico, flow cytometry at 13 years of age demonstrated markedly decreased CD40L expression (~32% of normal control) that retained the capacity to bind soluble CD40-Ig, suggesting that the mutation impairs CD40L surface expression without affecting its affinity for CD40. This case highlights the variability in the clinical evolution and phenotype of CD40L deficiency.
Department of Pediatric Immunology, Ege University, Faculty of Medicine, Erzene Mh., 35040 Izmir, Turkey.
Nurşen C
NC
Günaydin
Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, USA.
Janet
J
Chou
Department of Pediatric Immunology, Ege University, Faculty of Medicine, Erzene Mh., 35040 Izmir, Turkey.
Neslihan E
NE
Karaca
Department of Pediatric Immunology, Ege University, Faculty of Medicine, Erzene Mh., 35040 Izmir, Turkey.
Güzide
G
Aksu
Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, USA.
Michel J
MJ
Massaad
Department of Pediatric Immunology, Ege University, Faculty of Medicine, Erzene Mh., 35040 Izmir, Turkey.
Elif
E
Azarsiz
Ege University, Faculty of Medicine, Department of Pathology, Izmir, Turkey.
Yesim
Y
Ertan
Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, USA. Electronic address: raif.geha@childrens.harvard.edu.
Raif S
RS
Geha
Department of Pediatric Immunology, Ege University, Faculty of Medicine, Erzene Mh., 35040 Izmir, Turkey. Electronic address: necil.kutukculer@ege.edu.tr.
Necil
N
Kütükçüler
D000293:Adolescent; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics* / Q000378:metabolism; D002574:Cervical Vertebrae / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D003937:Diagnosis, Differential; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009442:Neurilemmoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011859:Radiography; D013125:Spinal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
D019013:CD40 Antigens; D023201:CD40 Ligand
CD40 ligand; Common variable immunodeficiency; Schwannoma