Structural basis for red cell phenotypic changes in newly identified, naturally occurring subgroup mutants of the human blood group B glycosyltransferase.
(2007) In Transfusion 47(5). p.864-875- Abstract
- BACKGROUND: Four amino-acid-changing polymorphisms differentiate the blood group A and B alleles. Multiple missense mutations are associated with weak expression of A and B antigens but the structural changes causing subgroups have not been studied. STUDY DESIGN AND METHODS: Individuals or families having serologically weak B antigen on their red cells were studied. Alleles were characterized by sequencing of exons 1 through 7 in the ABO gene. Single crystal X-ray diffraction, three-dimensional-structure molecular modeling, and enzyme kinetics showed the effects of the B allele mutations on the glycosyltransferases. RESULTS: Seven unrelated individuals with weak B phenotypes possessed seven different B alleles, five of which are new and... (More)
- BACKGROUND: Four amino-acid-changing polymorphisms differentiate the blood group A and B alleles. Multiple missense mutations are associated with weak expression of A and B antigens but the structural changes causing subgroups have not been studied. STUDY DESIGN AND METHODS: Individuals or families having serologically weak B antigen on their red cells were studied. Alleles were characterized by sequencing of exons 1 through 7 in the ABO gene. Single crystal X-ray diffraction, three-dimensional-structure molecular modeling, and enzyme kinetics showed the effects of the B allele mutations on the glycosyltransferases. RESULTS: Seven unrelated individuals with weak B phenotypes possessed seven different B alleles, five of which are new and result in substitution of highly conserved amino acids: M189V, I192T, F216I, D262N, and A268T. One of these (F216I) was due to a hybrid allele resulting from recombination between B and O-1v alleles. The two other alleles were recently described in other ethnic groups and result in V175M and L232P. The first crystal-structure determination (A268T) of a subgroup glycosyltransferase and molecular modeling (F216I, D262N, L232P) indicated conformational changes in the enzyme that could explain the diminished enzyme activity. The effect of three mutations could not be visualized since they occur in a disordered loop. CONCLUSION: The genetic background for B-w phenotypes is very heterogeneous but usually arises through seemingly random missense mutations throughout the last ABO exon. The targeted amino acid residues, however, are well conserved during evolution. Based on analysis of the resulting structural changes in the glycosyltransferase, the mutations are likely to disrupt molecular bonds of importance for enzymatic function. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/167327
- author
- Hosseini Maaf, Bahram
LU
; Letts, James A
; Persson, Mattias
; Smart, Elizabeth
; Lepennec, Pierre-Yves
; Hustinx, Hein
; Zhao, Zhihon
; Palcic, Monica M
; Evans, Stephen V
; Chester, Alan
LU
and Olsson, Martin L
LU
(Less) - organization
- publishing date
- 2007
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Transfusion
- volume
- 47
- issue
- 5
- pages
- 864 - 875
- publisher
- Wiley-Blackwell
- external identifiers
-
- wos:000245992700018
- scopus:34247617415
- pmid:17465952
- ISSN
- 1537-2995
- DOI
- 10.1111/j.1537-2995.2007.01203.x
- language
- English
- LU publication?
- yes
- id
- 23b386a6-099d-4376-a0ab-6a3ce07c892d (old id 167327)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17465952&dopt=Abstract
- date added to LUP
- 2016-04-01 16:15:18
- date last changed
- 2022-01-28 18:23:10
@article{23b386a6-099d-4376-a0ab-6a3ce07c892d,
abstract = {{BACKGROUND: Four amino-acid-changing polymorphisms differentiate the blood group A and B alleles. Multiple missense mutations are associated with weak expression of A and B antigens but the structural changes causing subgroups have not been studied. STUDY DESIGN AND METHODS: Individuals or families having serologically weak B antigen on their red cells were studied. Alleles were characterized by sequencing of exons 1 through 7 in the ABO gene. Single crystal X-ray diffraction, three-dimensional-structure molecular modeling, and enzyme kinetics showed the effects of the B allele mutations on the glycosyltransferases. RESULTS: Seven unrelated individuals with weak B phenotypes possessed seven different B alleles, five of which are new and result in substitution of highly conserved amino acids: M189V, I192T, F216I, D262N, and A268T. One of these (F216I) was due to a hybrid allele resulting from recombination between B and O-1v alleles. The two other alleles were recently described in other ethnic groups and result in V175M and L232P. The first crystal-structure determination (A268T) of a subgroup glycosyltransferase and molecular modeling (F216I, D262N, L232P) indicated conformational changes in the enzyme that could explain the diminished enzyme activity. The effect of three mutations could not be visualized since they occur in a disordered loop. CONCLUSION: The genetic background for B-w phenotypes is very heterogeneous but usually arises through seemingly random missense mutations throughout the last ABO exon. The targeted amino acid residues, however, are well conserved during evolution. Based on analysis of the resulting structural changes in the glycosyltransferase, the mutations are likely to disrupt molecular bonds of importance for enzymatic function.}},
author = {{Hosseini Maaf, Bahram and Letts, James A and Persson, Mattias and Smart, Elizabeth and Lepennec, Pierre-Yves and Hustinx, Hein and Zhao, Zhihon and Palcic, Monica M and Evans, Stephen V and Chester, Alan and Olsson, Martin L}},
issn = {{1537-2995}},
language = {{eng}},
number = {{5}},
pages = {{864--875}},
publisher = {{Wiley-Blackwell}},
series = {{Transfusion}},
title = {{Structural basis for red cell phenotypic changes in newly identified, naturally occurring subgroup mutants of the human blood group B glycosyltransferase.}},
url = {{http://dx.doi.org/10.1111/j.1537-2995.2007.01203.x}},
doi = {{10.1111/j.1537-2995.2007.01203.x}},
volume = {{47}},
year = {{2007}},
}