Genetic analysis and protein modeling evaluation of a novel FUT1 variant c.683T>C (p.Met228Thr) in a Chinese individual with para‐Bombay phenotype

Abstract Background The para‐Bombay phenotype is a rare red blood cell phenotype characterized by the absence or reduction of ABH antigens on red blood cells but the presence of ABH substances in saliva. Materials and Methods Red blood cells were phenotyped by standard serology methods. The CDS region of ABO , FUT1 , and FUT2 was amplified with polymerase chain reaction and then directly sequenced. Haplotypes of FUT1 were identified by TA cloning sequencing. Three‐dimensional (3D) structural analysis of wild‐type and mutant fucosyltransferases was built and analyzed using Phyre2 and Pymol software. The effect of the novel substitution on the function of fucosyltransferase was evaluated by PROVEAN and Polyphen‐2. Results Weak A but no B and H antigens were detected on the surface of red blood cells of the proband. Sequencing and cloning analysis found that the proband carried a novel FUT1 variant (c.683T>C, p.Met228Thr). 3D model showed that the p.Met228Thr variant in the enzyme caused a certain angle of steering and displacement of the α‐helices where residue 228 was located, and the effect of this substitution was predicted to be deleterious and probably damaging, which suggested that the local spatial conformation and activity of the enzyme might be significantly affected. Conclusion A novel FUT1 variant that may result in substantially reduced activity of alpha‐1,2‐fucosyltransferase T1 ( α 2FucT1) was identified, and computational evaluation indicated that Met228 was a critical site for the function of α 2FucT1, which was also supported by two already published defective alleles FUT1*01W.12 (c.682A>G, p.Met228Val) and FUT1*01N.18 (c.684G>A, p.Met228Ile).