Characterization of nine novel mutations in the CD40 ligand gene in patients with x-linked hyper IgM syndrome of various ancestry

P. Macchi, A. Villa, D. Strina, M. G. Sacco, F. Morali, D. Brugnoni, S. Giliani, E. Mantuano, A. Fasth, B. Andersson, B. J M Zegers, G. Cavagni, I. Reznick, J. Levy, I. Zan-Bar, Y. Porat, P. Airo, A. Plebani, P. Vezzoni, L. D. Notarangelo

Research output: Contribution to journalArticle

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Abstract

X-linked immunodeficiency with hyper-IgM (HIGMX-1) is a rare disorder caused by defective expression of the CD40 ligand (CD40L) by activated T lymphocytes, resulting in inefficient T-B cell cooperation and failure of B cells to undergo immunoglobulin isotype switch. In the present work, we describe nine patients of various ancestry who bear different mutations in the X chromosome-specific CD40L gene. Two of the mutations were nonsense mutations, one each resulting in premature stop codons at amino acid residues 39 and 140. Three patients had single point missense mutations, one each at codons 126, 140, and 144. Another patient had a 4-bp genomic deletion in exon 2, resulting in a frameshift and premature termination. Three patients showed insertions, one each of 1, 2, and 4 nt, probably because of polymerase slippage, resulting in frameshift mutation and premature termination. Overall, these observations confirm the heterogeneity of mutations in HIGMX- 1. However, the identification of two patients whose mutation involves codon 140 (previously shown to be altered in two other unrelated subjects) suggests that this may be a hotspot of mutation in HIGMX-1. In two additional patients with clinical and immunological features indistinguishable from canonical HIGMX-1, no mutation was detected in the coding sequence, in the 5' flanking region, or in the 3' UTR.

Original languageEnglish
Pages (from-to)898-906
Number of pages9
JournalAmerican Journal of Human Genetics
Volume56
Issue number4
Publication statusPublished - 1995

Fingerprint

Hyper-IgM Immunodeficiency Syndrome
CD40 Ligand
Mutation
Genes
Nonsense Codon
Codon
Type 1 Hyper-IgM Immunodeficiency Syndrome
B-Lymphocytes
Frameshift Mutation
Immunoglobulin Isotypes
5' Flanking Region
X Chromosome
3' Untranslated Regions
Missense Mutation
Point Mutation
Exons
T-Lymphocytes
Amino Acids

ASJC Scopus subject areas

  • Genetics

Cite this

Characterization of nine novel mutations in the CD40 ligand gene in patients with x-linked hyper IgM syndrome of various ancestry. / Macchi, P.; Villa, A.; Strina, D.; Sacco, M. G.; Morali, F.; Brugnoni, D.; Giliani, S.; Mantuano, E.; Fasth, A.; Andersson, B.; Zegers, B. J M; Cavagni, G.; Reznick, I.; Levy, J.; Zan-Bar, I.; Porat, Y.; Airo, P.; Plebani, A.; Vezzoni, P.; Notarangelo, L. D.

In: American Journal of Human Genetics, Vol. 56, No. 4, 1995, p. 898-906.

Research output: Contribution to journalArticle

Macchi, P, Villa, A, Strina, D, Sacco, MG, Morali, F, Brugnoni, D, Giliani, S, Mantuano, E, Fasth, A, Andersson, B, Zegers, BJM, Cavagni, G, Reznick, I, Levy, J, Zan-Bar, I, Porat, Y, Airo, P, Plebani, A, Vezzoni, P & Notarangelo, LD 1995, 'Characterization of nine novel mutations in the CD40 ligand gene in patients with x-linked hyper IgM syndrome of various ancestry', American Journal of Human Genetics, vol. 56, no. 4, pp. 898-906.
Macchi, P. ; Villa, A. ; Strina, D. ; Sacco, M. G. ; Morali, F. ; Brugnoni, D. ; Giliani, S. ; Mantuano, E. ; Fasth, A. ; Andersson, B. ; Zegers, B. J M ; Cavagni, G. ; Reznick, I. ; Levy, J. ; Zan-Bar, I. ; Porat, Y. ; Airo, P. ; Plebani, A. ; Vezzoni, P. ; Notarangelo, L. D. / Characterization of nine novel mutations in the CD40 ligand gene in patients with x-linked hyper IgM syndrome of various ancestry. In: American Journal of Human Genetics. 1995 ; Vol. 56, No. 4. pp. 898-906.
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abstract = "X-linked immunodeficiency with hyper-IgM (HIGMX-1) is a rare disorder caused by defective expression of the CD40 ligand (CD40L) by activated T lymphocytes, resulting in inefficient T-B cell cooperation and failure of B cells to undergo immunoglobulin isotype switch. In the present work, we describe nine patients of various ancestry who bear different mutations in the X chromosome-specific CD40L gene. Two of the mutations were nonsense mutations, one each resulting in premature stop codons at amino acid residues 39 and 140. Three patients had single point missense mutations, one each at codons 126, 140, and 144. Another patient had a 4-bp genomic deletion in exon 2, resulting in a frameshift and premature termination. Three patients showed insertions, one each of 1, 2, and 4 nt, probably because of polymerase slippage, resulting in frameshift mutation and premature termination. Overall, these observations confirm the heterogeneity of mutations in HIGMX- 1. However, the identification of two patients whose mutation involves codon 140 (previously shown to be altered in two other unrelated subjects) suggests that this may be a hotspot of mutation in HIGMX-1. In two additional patients with clinical and immunological features indistinguishable from canonical HIGMX-1, no mutation was detected in the coding sequence, in the 5' flanking region, or in the 3' UTR.",
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T1 - Characterization of nine novel mutations in the CD40 ligand gene in patients with x-linked hyper IgM syndrome of various ancestry

AU - Macchi, P.

AU - Villa, A.

AU - Strina, D.

AU - Sacco, M. G.

AU - Morali, F.

AU - Brugnoni, D.

AU - Giliani, S.

AU - Mantuano, E.

AU - Fasth, A.

AU - Andersson, B.

AU - Zegers, B. J M

AU - Cavagni, G.

AU - Reznick, I.

AU - Levy, J.

AU - Zan-Bar, I.

AU - Porat, Y.

AU - Airo, P.

AU - Plebani, A.

AU - Vezzoni, P.

AU - Notarangelo, L. D.

PY - 1995

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