Missense mutations in the C-terminal portion of the B4GALNT2-encoded glycosyltransferase underlying the Sd(a-) phenotype.
Biochem Biophys Rep
; 19: 100659, 2019 Sep.
Article
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| MEDLINE
| ID: mdl-31367682
ABSTRACT
Sda is a high-frequency carbohydrate histo-blood group antigen, GalNAcß1-4(NeuAcα2-3)Galß, implicated in pathogen invasion, cancer, xenotransplantation and transfusion medicine. Complete lack of this glycan epitope results in the Sd(a-) phenotype observed in 4% of individuals who may produce anti-Sda. A candidate gene (B4GALNT2), encoding a Sda-synthesizing ß-1,4-N-acetylgalactosaminyltransferase (ß4GalNAc-T2), was cloned in 2003 but the genetic basis of human Sda deficiency was never elucidated. Experimental and bioinformatic approaches were used to identify and characterize B4GALNT2 variants in nine Sd(a-) individuals. Homozygosity for rs7224888Tâ¯>â¯C dominated the cohort (nâ¯=â¯6) and causes p.Cys466Arg, which targets a highly conserved residue located in the enzymatically active domain and is judged deleterious to ß4GalNAc-T2. Its allele frequency was 0.10-0.12 in different cohorts. A Sd(a-) compound heterozygote combined rs7224888Tâ¯>â¯C with a splice-site mutation, rs72835417Gâ¯>â¯A, predicted to alter splicing and occurred at a frequency of 0.11-0.12. Another compound heterozygote had two rare nonsynonymous variants, rs148441237Aâ¯>â¯G (p.Gln436Arg) and rs61743617Câ¯>â¯T (p.Arg523Trp), in trans. One sample displayed no differences compared to Sd(a+). When investigating linkage disequilibrium between B4GALNT2 variants, we noted a 32-kb block spanning intron 9 to the intergenic region downstream of B4GALNT2. This block includes RP11-708H21.4, a long non-coding RNA recently reported to promote tumorigenesis and poor prognosis in colon cancer. The expression patterns of B4GALNT2 and RP11-708H21.4 correlated extremely well in >1000 cancer cell lines. In summary, we identified a connection between variants of the cancer-associated B4GALNT2 gene and Sda, thereby establishing a new blood group system and opening up for the possibility to predict Sd(a+) and Sd(aâ) phenotypes by genotyping.
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01-internacional
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MEDLINE
Idioma:
En
Revista:
Biochem Biophys Rep
Año:
2019
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Article
País de afiliación:
Suecia