Yazarlar : Francis NJ, McNicholas B, Awan A, Waldron M, Reddan D, Sadlier D, Kavanagh D, Strain L, Marchbank KJ, Harris CL, Goodship TH.

Yayın : Blood.

Yayın Yılı : 2011

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/22058112

Konu : Diğer

Literatür İçeriği :  

Abstract

Genomic disorders affecting the genes encoding factor H (fH) and the five factor H related proteins have been described in association with atypical hemolytic uremic syndrome (aHUS). These include deletions of CFHR3, CFHR1 and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through non-allelic homologous recombination (NAHR) secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification (MLPA) to screen for such genomic disorders we have identified a large aHUS family where a deletion has occurred through microhomology-mediated end joining (MMEJ) rather than NAHR. In the three affected individuals of this family we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein which is secreted with normal fluid phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of factor H at the cell surface is critically dependent on the structural integrity of the whole molecule

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