SOMATIC-CELL SELECTION IS A MAJOR DETERMINANT OF THE BLOOD-CELL PHENOTYPE IN HETEROZYGOTES FOR GLUCOSE-6-PHOSPHATE-DEHYDROGENASE MUTATIONS CAUSING SEVERE ENZYME DEFICIENCY
S. Filosa et al., SOMATIC-CELL SELECTION IS A MAJOR DETERMINANT OF THE BLOOD-CELL PHENOTYPE IN HETEROZYGOTES FOR GLUCOSE-6-PHOSPHATE-DEHYDROGENASE MUTATIONS CAUSING SEVERE ENZYME DEFICIENCY, American journal of human genetics, 59(4), 1996, pp. 887-895
X-chromosome inactivation in mammals is regarded as an essentially ran
dom process, but the resulting somatic-cell mosaicism creates the oppo
rtunity for cell selection. In most people with red-blood-cell glucose
-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme-deficient phe
notype is only moderately expressed in nucleated cells. However, in a
small subset of hemizygous males who suffer from chronic nonspherocyti
c hemolytic anemia, the underlying mutations (designated class I) caus
e more-severe G6PD deficiency, and this might provide an opportunity f
or selection in heterozygous females during development. In order to t
est this possibility we have analyzed four heterozygotes for class I G
6PD mutations: two with G6PD Portici (1178G-->A) and two with G6PD Bar
i (1187C-->T). We found that in fractionated blood cell types (includi
ng erythroid, myeloid, and lymphoid cell lineages) there was a signifi
cant excess of G6PD-normal cells. The significant concordance that we
have observed in the degree of imbalance in the different blood-cell l
ineages indicates that a selective mechanism is likely to operate at t
he level of pluripotent blood stem cells. Thus, it appears that severe
G6PD deficiency affects adversely the proliferation or the survival o
f nucleated blood cells and that this phenotypic characteristic is cri
tical during hematopoiesis.