Figure 3. X-linked dominant LOF ALAS2 mutations can result in macrocytosis and dyserythropoiesis through cell-nonautonomous effects.

(A) Sequencing of cDNA derived from cultured erythroid cells from the proband showed skewing toward the WT ALAS2 allele at the late stages of erythroid differentiation. Cells began as progenitors (day 5), became intermediate erythroblasts (day 9), and transitioned to orthochromatic erythroblasts (day 14). By late erythropoiesis, only a trace amount of the mutant allele was detectable. (B) Model showing how developing erythroid progenitors and precursors compete for space within the BM. The active X chromosome expressed in each group of cells (brown and pink for the mutant and WT, respectively) is shown in blue, with some cells expressing the mutant (red) and others expressing the WT (green) allele.