Compound heterozygosity of two novel RHAG alleles leads to a considerable disruption of the Rh complex

The Rhesus (Rh) complex consists of a core comprising the Rh proteins (RhD/RhCE) and the Rh-associated glycoprotein ( RhAG) with accessory chains (GPB, LW, CD47). Molecular defects of the RHAGgene may cause a regulator Rhnull phenotype without Rh antigen expression or a Rhmod phenotype with decreased Rh antigen expression.Blood samples of a donor with strongly diminished Rh antigens and five family members were analyzed by serological phenotyping, flow cytometry, molecular testing, and gene expression analysis of Rh complex candidate genes.RHAG sequencing identified a missense mutation, c.241G>C (p.Gly81Arg) and a splice site mutation, c.640 + 3del14, among the cohort. Compound heterozygosityof these novel alleles identified in the propositus and two siblings gave rise to a strongly diminished expression of RhAG, Rh, and CD47antigens on the RBC surface.The Rhmod phenotype was caused by a novel RHAG splice site mutationin association with a non-functional allele. The primary depression of RhAGis most likely due to posttranslational events that affect the interaction and processing of the RhAGglycoprotein and gave rise to a secondary depression of RhD, RhCE, and CD47, the major members of the Rh complex.