SMYD1 is the underlying gene for the AnWj-negative blood group phenotype

Eur J Haematol. 2018 Oct;101(4):496-501. doi: 10.1111/ejh.13133. Epub 2018 Aug 3.

Abstract

Background: AnWj is a high-incidence blood group antigen associated with three clinical disorders: lymphoid malignancies, immunologic disorders, and autoimmune hemolytic anemia. The aim of this study was to determine the genetic basis of an inherited AnWj-negative phenotype.

Methods: We identified a consanguineous family with two AnWj-negative siblings and 4 additional AnWj-negative individuals without known familial relationship to the index family. We performed exome sequencing in search for rare homozygous variants shared by the two AnWj-negative siblings of the index family and searched for these variants in the four non-related AnWj-negative individuals.

Results: Exome sequencing revealed seven candidate genes that showed complete segregation in the index family and for which the two AnWj-negative siblings were homozygous. However, the four additional non-related AnWj-negative subjects were homozygous for only one of these variants, rs114851602 (R320Q) in the SMYD1 gene. Considering the frequency of the minor allele, the chance of randomly finding 4 consecutive such individuals is 2.56 × 10-18 .

Conclusion: We present genetic and statistical evidence that the R320Q substitution in SMYD1 underlies an inherited form of the AnWj-negative blood group phenotype. The mechanism by which the mutation leads to this phenotype remains to be determined.

Keywords: AnWj; R320Q; SMYD1; blood group antigen; exome sequencing; hematopoiesis; lymphoproliferative diseases; red cell disorders.

MeSH terms

  • Adult
  • Blood Group Antigens / chemistry
  • Blood Group Antigens / genetics*
  • Blood Group Antigens / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Erythrocytes / immunology
  • Erythrocytes / metabolism
  • Evolution, Molecular
  • Female
  • Gene Frequency
  • Genetic Variation
  • Genotype
  • Humans
  • Male
  • Models, Molecular
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics*
  • Pedigree
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Protein Conformation
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Whole Exome Sequencing

Substances

  • Blood Group Antigens
  • DNA-Binding Proteins
  • Muscle Proteins
  • SMYD1 protein, human
  • Transcription Factors