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Editorials
cell mosaicism could be important for the patients, who are not regularly informed of the incidental finding. Because the technologies required to confirm mosaicism lie far out- side routine procedures, they are not available to clinical laboratories because of the limited resources available. This was not the case for these 2 patients5 whose pathophysiol- ogy was examined in unusual detail.
The current study5 represents a step forward in this field, as the exact types of precursors, affected by distinct somatic mutations, have been determined. LOH was, indeed, the underlying cause in both patients, affecting the RH locus on the short arm of chromosome 1 and encompassing at least 26.7 and 42.4 Mb, respectively. Such large deletions of parts of a chromosome are considered rare in patients without malignancies or other hematologic pathologies. The RHCE gene spans only 60 kb and an RHCE deletion is still extremely rare in genomic DNA. As both large deletions encompassed the RHD/RHCE gene loci, they explained the serological phenotype with the loss of the c antigen in approximately 50% of the patients’ red cells (Figure 1).
Besides the deletion of a chromosomal segment or a whole gene, less intrusive mechanisms, all the way down to 1 single nucleotide polymorphism (SNP), can functional- ly mimic the same LOH for RHCE, which prompted the authors to study these 2 patients. Like any DNA variation, somatic mutations,14 if found in exons, can affect the pro- tein by missense and non-functional mutations, and less so by silent mutations. A novel SNP in a somatic cell lineage occurs much more frequently than any huge alteration affecting long DNA segments,5 but can be as important for the blood group phenotype.15 A SNP may also have an impact on gene regulation when occurring in the introns, the 3’- or 5’-untranslated regions of a gene, or somewhere in the long DNA segments interspersed between genes. Genes differ in their propensity to lose their function,16 as do the mechanism causing changes, ranging from an SNP in an RH gene,17 to large deletions affecting the RH gene locus18,19 and adjacent genes.5,13
Somatic mosaicism is always acquired and occurs during mitosis in 1 cell lineage derived from 1 zygote, often after
Figure 1. Schematic repre- sentation of differentiation from early stem to red cells. A model for normal hematopoiesis (top) assumes equal cell division at all stages (lines with open circles). In the models for early (middle) and late (bottom) mosaicism, the red cells eventually reach 50% clonality. Some cell lin- eages are squeezed out, possibly experiencing apop- tosis (closed circles) before differentiating into red cells. This 50% mosaicism represents the red cell pop- ulations actually observed in the peripheral blood of the 2 patients in the study by Dauber et al.5 reported in this issue of the Journal.
haematologica | 2019; 1043)