ABCMdb

ABCB6 p.Arg276Trp

Predicted by SNAP2:	A: D (85%), C: D (80%), D: D (91%), E: D (85%), F: D (91%), G: D (85%), H: D (85%), I: D (85%), K: N (66%), L: D (85%), M: D (85%), N: D (80%), P: D (91%), Q: D (75%), S: D (80%), T: D (85%), V: D (91%), W: D (95%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] The ABCB6 mutation p.Arg192Trp is a recessive muta... Vox Sang. 2012 Sep 10. doi: 10.1111/j.1423-0410.2012.01650.x. Saison C, Helias V, Peyrard T, Merad L, Cartron JP, Arnaud L
The ABCB6 mutation p.Arg192Trp is a recessive mutation causing the Lan- blood type.
Vox Sang. 2012 Sep 10. doi: 10.1111/j.1423-0410.2012.01650.x., [PMID:22958180]

Abstract [show]
Background and Objective The membrane transporter ABCB6 has recently been shown to carry the high-frequency red-blood-cell (RBC) antigen Lan. All the Lan- individuals genotyped so far have inherited two recessive null mutations in ABCB6. The finding of a family with the Lan- blood type occurring in two successive generations prompted this study. Methods Mutations in ABCB6 were searched by Sanger sequencing of exons and flanking intronic regions. Expression analysis of the Lan antigen was carried out by serology and flow cytometry. PCR-RFLP genotyping and Western blot analysis were also applied. Results All the Lan- members of this family were homozygous for c.574C>T, p.Arg192Trp in ABCB6 while the Lan+ members were heterozygous for this missense mutation encoded by the SNP rs149202834. Homozygosity for p.Arg192Trp was associated not only with absence of the Lan antigen, but also of the ABCB6 transporter in RBC membrane. The complete absence of Lan expression resulting from p.Arg192Trp homozygosity was confirmed by the subsequent identification of five unrelated Lan- individuals who were homozygous for this mutation and who developed an anti-Lan. We also provide evidence that three other single amino acid mutations in ABCB6 (c.826C >T, p.Arg276Trp; c.85_87delTTC, p.Phe29del; c.1762G >A, p.Gly588Ser) may also define ABCB6 null alleles. Conclusion p.Arg192Trp is the first ABCB6 missense mutation causing the Lan- blood type and appears to be a relatively frequent cause of this rare blood type. Like the previously reported frameshift, nonsense and essential splice-site mutations in ABCB6, this missense mutation is recessive and defines an ABCB6 null allele. Other single amino acid mutations in ABCB6 may also cause the Lan- blood type.

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No. Sentence Comment
9 We also provide evidence that three other single amino acid mutations in ABCB6 (c.826C >T, p.Arg276Trp; c.85_87delTTC, p.Phe29del; c.1762G >A, p.Gly588Ser) may also define ABCB6 null alleles. Login to comment
50 The pCEP5 plasmids corresponding to ABCB6 p.Arg192Trp, p.Arg648Ter, p.Arg276Trp, p.Gly588Ser and p.Phe29del were similarly constructed by using fully sequenced NotI / SbfI fragments corresponding to mutant coding sequences of ABCB6 cDNA generated by site-directed mutagenesis of the pCR4-ABCB6-dUTR plasmid. Login to comment
97 Sequencing of ABCB6 revealed that donor BAR was heterozygous for p.Arg276Trp (c.826C>T), donor GAR was heterozygous for p.Phe29del (c.85_87delTTC) and donor LIN was heterozygous for p.Gly588Ser (c.1762G>A). Login to comment
98 Of note, p.Arg276Trp and p.Gly588Ser corresponded to the minor alleles of rs57467915 and rs145526996, respectively, and both were predicted to be as 'damaging` as p.Arg192Trp by the SIFT and POLYPHEN softwares [5, 6]. Login to comment
99 Towards demonstrating that p.Arg276Trp, p.Phe29del and p.Gly588Ser were responsible for the partial lack of expression of the Lan antigen in these three blood donors, we used the aforementioned heterologous expression system. Surprisingly, only p.Phe29del prevented the expression of the Lan antigen (Fig. 3b). Login to comment
100 This result indicated that the single amino acid change resulting from p.Arg276Trp and p.Gly588Ser, contrary to p.Arg192Trp and p.Phe29del, could not by themselves account for reduced levels of the Lan antigen or the ABCB6 transporter. Login to comment
101 While c.826C>T (p.Arg276Trp) and c.1762G>A (p.Gly588Ser) might induce degradation of ABCB6 mRNA or a splicing defect, we could not rule out that these two mutations were completely unrelated to the lack of expression of the Lan antigen that we observed in the corresponding blood donors. Login to comment
103 Though incomplete, all these data suggested that p.Arg276Trp, p.Phe29del and p.Gly588Ser also define null alleles of ABCB6. Login to comment
126 p.Arg276Trp, p.Phe29del and p.Gly588Ser are reminiscent of p.Arg192Trp that we have characterized as an ABCB6 null mutation. Login to comment
128 In contrast, we observed no effect of p.Arg276Trp and p.Gly588Ser on the expression of the Lan antigen in this heterologous system, suggesting that another molecular mechanism, yet unknown, is involved. Login to comment
131 We also provide partial evidence that p.Arg276Trp, p.Phe29del and p.Gly588Ser may also define ABCB6 null alleles, expecting that other laboratories genotyping Lan) individuals may confirm our results in the future. Login to comment
149 G l y 5 8 8 S e r WB1 ABCB6 WB2 p55 ABCB6 p.Gly588Ser ABCB6 p.Phe29del ABCB6 p.Arg276Trp (a) (b) Fig. 3 Characterization of three ABCB6 mutations potentially responsible for the Lan) blood type. Login to comment
150 (a) Western blot analysis of ABCB6 in blood donors who were heterozygous for p.Arg276Trp (lane 1), for p.Phe29del (lane 3), for p.Gly588Ser (lane 5) or wild type (lanes 2 and 4). Login to comment
152 (b) Study of p.Arg276Trp, p.Phe29del and p.Gly588Ser in the heterologous expression system for the Lan antigen as in Fig. 2. Login to comment