Somatic-cell selection is a major determinant of the blood-cell phenotype in heterozygotes for glucose-6-phosphate dehydrogenase mutations causing severe enzyme deficiency

Stefania Filosa, Nunzia Giacometti, Cai Wangwei, Domenico De Mattia, David Pagnini, Fiorella Alfinito, Francesco Schettini, Lucio Luzzatto, Giuseppe Martini

Research output: Contribution to journalArticlepeer-review

Abstract

X-chromosome inactivation in mammals is regarded as an essentially random process, but the resulting somatic-cell mosaicism creates the opportunity for cell selection. In most people with red-blood-cell glucose- 6-phosphate dehydrogenase (G6PD) deficiency, the enzyme-deficient phenotype is only moderately expressed in nucleated cells. However, in a small subset of hemizygous males who suffer from chronic nonspherocytic hemolytic anemia, the underlying mutations (designated class I) cause more-severe G6PD deficiency, and this might provide an opportunity for selection in heterozygous females during development. In order to test this possibility we have analyzed four heterozygotes for class I G6PD mutations: two with G6PD Portici (1178G→A) and two with G6PD Bari (1187C→T). We found that in fractionated blood cell types (including erythroid, myeloid, and lymphoid cell lineages) there was a significant excess of G6PD-normal cells. The significant concordance that we have observed in the degree of imbalance in the different blood-cell lineages indicates that a selective mechanism is likely to operate at the level of pluripotent blood stem cells. Thus, it appears that severe G6PD deficiency affects adversely the proliferation or the survival of nucleated blood cells and that this phenotypic characteristic is critical during hematopoiesis.

Original languageEnglish
Pages (from-to)887-895
Number of pages9
JournalAmerican Journal of Human Genetics
Volume59
Issue number4
Publication statusPublished - 1996

ASJC Scopus subject areas

  • Genetics

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