SOMATIC-CELL SELECTION IS A MAJOR DETERMINANT OF THE BLOOD-CELL PHENOTYPE IN HETEROZYGOTES FOR GLUCOSE-6-PHOSPHATE-DEHYDROGENASE MUTATIONS CAUSING SEVERE ENZYME DEFICIENCY

Citation
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
Citations number
65
Categorie Soggetti
Genetics & Heredity
ISSN journal
00029297
Volume
59
Issue
4
Year of publication
1996
Pages
887 - 895
Database
ISI
SICI code
0002-9297(1996)59:4<887:SSIAMD>2.0.ZU;2-N
Abstract
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.