Two populations of heterozygote erythrocytes in moderate hypoxanthine guanine phosphoribosyltransferase deficiency

Abstract

THE X-linked condition hypoxanthine guanine phosphoribosyltransferase (HGPRT) deficiency may be either gross or moderate in degree and is invariably associated with overproduction of urate in the hemizygote^1,2. In addition, however, the gross deficiency state (Lesch–Nyhan syndrome)³ also manifests with mental deficiency, choreoathetosis, spasticity and self-mutilation. Fibroblasts from heterozygotes for the gross deficiency state display mosaicism, some having normal HGPRT activity and others the reduced HGPRT activity characteristic of the hemizygote⁴. However, HGPRT activity in erythrocyte lysates from such heterozygotes is normal. Heterozygotes for the moderate HGPRT deficiency state, on the other hand, have HGPRT activity in erythrocyte lysates ranging between 20% of normal and completely normal values⁵. To elucidate this, we have developed an autoradiographic procedure to show HGPRT activity in individual erythrocytes. In families with moderate HGPRT deficiency, in whom erythrocytes of the hemizygote were not significantly labelled by this procedure, heterozygotes showed two erythrocyte populations, one deficient in HGPRT and one containing HGPRT activity. On the other hand, in families whose HGPRT deficiency was gross and manifested as the Lesch–Nyhan syndrome, heterozygotes showed only the normal pattern of labelling. Thus, mosaicism was present in erythrocytes from heterozygotes for moderate, but not for gross, HGPRT deficiency. The former finding supports the Lyon hypothesis⁶ whereas, the latter finding suggests that either the X chromosome carrying the mutant HGPRT gene is preferentially inactivated, or the X chromosome is randomly inactivated with later selection against the erythrocyte precursors containing the mutant HGPRT enzyme.