Manisha Madkaikar1, Maya Gupta2, Sushant Chavan2, Khushnooma Italia2, Mukesh Desai3, Rashid Merchant4, Nita Radhakrishnan5, Kanjaksha Ghosh2. 1. National Institute of Immunohaematology, KEM Hospital, 13th Floor, Parel, Mumbai 400012, India. Electronic address: madkaikarm@icmr.org.in. 2. National Institute of Immunohaematology, KEM Hospital, 13th Floor, Parel, Mumbai 400012, India. 3. Department of Immunology, Wadia Hospital, Parel, Mumbai 400012, India. 4. Nanavati Hospital, Mumbai 400056, India. 5. Ganga Ram Hospital, Delhi 110060, India.
Abstract
BACKGROUND: X-linked hyper-IgM (XHIM) is a primary immunodeficiency disorder characterized by recurrent infections, low serum IgG and IgA and normal or elevated IgM. It results from mutations in the CD40 ligand (CD40L) gene. Confirmation of diagnosis with identification of underlying molecular defect is important for the initiation of appropriate therapeutic interventions, including immunoglobulin replacement, antibiotics and bone marrow transplantation. METHODS: To investigate the molecular basis of XHIM, we evaluated 7 patients with suspected XHIM and abnormal CD40L expression on activated CD4(+) T lymphocytes. The entire coding region and intronic splice sites of the CD40L gene were sequenced from the genomic DNA of the patients. RESULTS: 7 mutations; 3 nonsense (c.172delA, c.A229T, c.C478T), 1 missense (c.A506G) and 3 splice sites [c.346+2(T→C), c.289-1(G→C), c.346+1(G→T)] were identified, out of which 5 were novel. CONCLUSION: A wide heterogeneity in the nature of mutations has been observed in Indian XHIM patients in the present study. Identification of mutations in this rare disorder will help in genetic diagnosis in affected families which could be further useful in prenatal diagnosis.
BACKGROUND:X-linked hyper-IgM (XHIM) is a primary immunodeficiency disorder characterized by recurrent infections, low serum IgG and IgA and normal or elevated IgM. It results from mutations in the CD40 ligand (CD40L) gene. Confirmation of diagnosis with identification of underlying molecular defect is important for the initiation of appropriate therapeutic interventions, including immunoglobulin replacement, antibiotics and bone marrow transplantation. METHODS: To investigate the molecular basis of XHIM, we evaluated 7 patients with suspected XHIM and abnormal CD40L expression on activated CD4(+) T lymphocytes. The entire coding region and intronic splice sites of the CD40L gene were sequenced from the genomic DNA of the patients. RESULTS: 7 mutations; 3 nonsense (c.172delA, c.A229T, c.C478T), 1 missense (c.A506G) and 3 splice sites [c.346+2(T→C), c.289-1(G→C), c.346+1(G→T)] were identified, out of which 5 were novel. CONCLUSION: A wide heterogeneity in the nature of mutations has been observed in Indian XHIM patients in the present study. Identification of mutations in this rare disorder will help in genetic diagnosis in affected families which could be further useful in prenatal diagnosis.
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Authors: M Dasouki; A Jabr; G AlDakheel; F Elbadaoui; A M Alazami; B Al-Saud; R Arnaout; H Aldhekri; I Alotaibi; H Al-Mousa; A Hawwari Journal: Clin Exp Immunol Date: 2020-07-21 Impact factor: 4.330