TY - JOUR
T1 - Hemolytically inactive C4B complement allotype caused by a proline to leucine mutation in the C5-binding site
AU - McLean, Robert H.
AU - Niblack, Gary
AU - Julian, Bruce
AU - Wang, Tao
AU - Wyatt, Robert
AU - Phillips, John A.
AU - Collins, Timothy S.
AU - Winkelstein, Jerry
AU - Valle, David
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1994/11/4
Y1 - 1994/11/4
N2 - The fourth component of complement (C4) is encoded by two highly homologous genes, C4A and C4B. Only one hemolytically inactive C4A allotype (C4A*6) has been reported. No hemolytically inactive C4B allotype has been described. We report the first hemolytically inactive (hi) allotype of C4B, C4B*1(hi). This unique variant was first recognized by hemolytic overlay assays and confirmed to segregate in the affected pedigree with the major histocompatibility complex haplotype A28,B35,CW4,DR6,C4A3,C4B1(hi), BFF,C2C. By single strand conformational polymorphism, we detected only a migration variant in exon 12 caused by a C to T transition in the second base of codon 459. This mutation results in a leucine substitution for proline (P459L) 1 residue downstream of a residue known to contribute to the C5-binding site. Allele-specific oligonucleotide analysis of samples demonstrated cosegregation of the mutation with the hemolytically inactive allotype in the affected pedigree. Site-directed mutagenesis and expression studies showed that the P459L mutation causes loss of hemolytic function. C4B*1(hi) is the first example of a circulating C4B protein lacking detectable hemolytic activity and the P459L mutation expands our knowledge of the C5-binding site of C4.
AB - The fourth component of complement (C4) is encoded by two highly homologous genes, C4A and C4B. Only one hemolytically inactive C4A allotype (C4A*6) has been reported. No hemolytically inactive C4B allotype has been described. We report the first hemolytically inactive (hi) allotype of C4B, C4B*1(hi). This unique variant was first recognized by hemolytic overlay assays and confirmed to segregate in the affected pedigree with the major histocompatibility complex haplotype A28,B35,CW4,DR6,C4A3,C4B1(hi), BFF,C2C. By single strand conformational polymorphism, we detected only a migration variant in exon 12 caused by a C to T transition in the second base of codon 459. This mutation results in a leucine substitution for proline (P459L) 1 residue downstream of a residue known to contribute to the C5-binding site. Allele-specific oligonucleotide analysis of samples demonstrated cosegregation of the mutation with the hemolytically inactive allotype in the affected pedigree. Site-directed mutagenesis and expression studies showed that the P459L mutation causes loss of hemolytic function. C4B*1(hi) is the first example of a circulating C4B protein lacking detectable hemolytic activity and the P459L mutation expands our knowledge of the C5-binding site of C4.
UR - http://www.scopus.com/inward/record.url?scp=0028151107&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028151107&partnerID=8YFLogxK
M3 - Article
C2 - 7961694
AN - SCOPUS:0028151107
SN - 0021-9258
VL - 269
SP - 27727
EP - 27731
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 44
ER -