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Genetic analysis of complement C1s deficiency associated with systemic lupus erythernatosus highlights alternative splicing of normal C1s gene

Amano, Mariane T; Ferriani, Virginia P L; Florido, Marlene P C; Reis, Ediniara S; Delcolli, Maria I M V; Azzolini, Ana E C S; Assis-Pandochi, Ana I; Sjöholm, Anders LU ; Farah, Chuck S and Jensenius, Jens C, et al. (2008) In Molecular Immunology 45(6). p.1693-1702
Abstract
Deficiencies of complement proteins of the classical pathway are strongly associated with the development of autoimmune diseases. Deficiency of Clr has been observed to occur concomitantly with deficiency in Cls and 9 out of 15 reported cases presented systemic lupus erythernatosus (SLE). Here, we describe a family in which all four children are deficient in Cls but only two of them developed SLE. Hemolytic activity mediated by the alternative and the lectin pathways were normal, but classical pathway activation was absent in all children's sera. Cls was undetectable, while in the parents' sera it was lower than in the normal controls. The levels of Clr observed in the siblings and parents sera were lower than in the control, while the... (More)
Deficiencies of complement proteins of the classical pathway are strongly associated with the development of autoimmune diseases. Deficiency of Clr has been observed to occur concomitantly with deficiency in Cls and 9 out of 15 reported cases presented systemic lupus erythernatosus (SLE). Here, we describe a family in which all four children are deficient in Cls but only two of them developed SLE. Hemolytic activity mediated by the alternative and the lectin pathways were normal, but classical pathway activation was absent in all children's sera. Cls was undetectable, while in the parents' sera it was lower than in the normal controls. The levels of Clr observed in the siblings and parents sera were lower than in the control, while the concentrations of other complement proteins (C3, C4, MBL and MASP-2) were normal in all family members. Impairment of Cls synthesis was observed in the patients' fibroblasts when analyzed by confocal microscopy. We show that all four siblings are homozygous for a mutation at position 938 in exon 6 of the Cls cDNA that creates a premature stop codon. Our investigations led us to reveal the presence of previously uncharacterized splice variants of Cls mRNA transcripts in normal human cells. These variants are derived from the skipping of exon 3 and from the use of an alternative 3' splice site within intron I which increases the size of exon 2 by 87 nucleotides. (Less)
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publication status
published
subject
keywords
autoinimunity, immunodeficiency diseases, complement, human, systemic, lupus erythernatosus
in
Molecular Immunology
volume
45
issue
6
pages
1693 - 1702
publisher
Pergamon
external identifiers
  • wos:000254181800016
  • scopus:38949191647
ISSN
1872-9142
DOI
10.1016/j.molimm.2007.09.034
language
English
LU publication?
yes
id
50c331c1-224a-4887-a466-7fdced296911 (old id 1184908)
date added to LUP
2008-09-02 14:20:26
date last changed
2017-04-09 03:54:33
@article{50c331c1-224a-4887-a466-7fdced296911,
  abstract     = {Deficiencies of complement proteins of the classical pathway are strongly associated with the development of autoimmune diseases. Deficiency of Clr has been observed to occur concomitantly with deficiency in Cls and 9 out of 15 reported cases presented systemic lupus erythernatosus (SLE). Here, we describe a family in which all four children are deficient in Cls but only two of them developed SLE. Hemolytic activity mediated by the alternative and the lectin pathways were normal, but classical pathway activation was absent in all children's sera. Cls was undetectable, while in the parents' sera it was lower than in the normal controls. The levels of Clr observed in the siblings and parents sera were lower than in the control, while the concentrations of other complement proteins (C3, C4, MBL and MASP-2) were normal in all family members. Impairment of Cls synthesis was observed in the patients' fibroblasts when analyzed by confocal microscopy. We show that all four siblings are homozygous for a mutation at position 938 in exon 6 of the Cls cDNA that creates a premature stop codon. Our investigations led us to reveal the presence of previously uncharacterized splice variants of Cls mRNA transcripts in normal human cells. These variants are derived from the skipping of exon 3 and from the use of an alternative 3' splice site within intron I which increases the size of exon 2 by 87 nucleotides.},
  author       = {Amano, Mariane T and Ferriani, Virginia P L and Florido, Marlene P C and Reis, Ediniara S and Delcolli, Maria I M V and Azzolini, Ana E C S and Assis-Pandochi, Ana I and Sjöholm, Anders and Farah, Chuck S and Jensenius, Jens C and Isaac, Lourdes},
  issn         = {1872-9142},
  keyword      = {autoinimunity,immunodeficiency diseases,complement,human,systemic,lupus erythernatosus},
  language     = {eng},
  number       = {6},
  pages        = {1693--1702},
  publisher    = {Pergamon},
  series       = {Molecular Immunology},
  title        = {Genetic analysis of complement C1s deficiency associated with systemic lupus erythernatosus highlights alternative splicing of normal C1s gene},
  url          = {http://dx.doi.org/10.1016/j.molimm.2007.09.034},
  volume       = {45},
  year         = {2008},
}