Two populations of heterozygote erythrocytes in moderate hypoxanthine guanine phosphoribosyltransferase deficiency
Two populations of heterozygote erythrocytes in moderate hypoxanthine guanine phosphoribosyltransferase deficiency
复制标题
中度次黄嘌呤鸟嘌呤磷酸核糖转移酶缺陷的两个杂合红细胞群体
作者：
L. A. Johnson;R. Gordon;B. Emmerson
X-连锁条件次黄嘌呤鸟嘌呤磷酸核糖基转移酶（HGPRT）缺乏症可能是严重或中度的，总是与半合子中尿酸盐的过度产生有关1，2。然而，除此之外，严重缺陷状态（Lesch-Nyhan综合征）3还表现为智力缺陷、舞蹈手足徐动症、痉挛和自残。来自严重缺陷状态的杂合子的成纤维细胞显示嵌合体，一些具有正常的HGPRT活性，另一些具有半合子特征的HGPRT活性降低4。然而，HGPRT活性在红细胞裂解物从这样的杂合子是正常的。另一方面，中度HGPRT缺乏状态的杂合子在红细胞裂解物中的HGPRT活性范围为正常值的20%至完全正常值5。为了阐明这一点，我们已经开发了一种放射自显影程序，以显示HGPRT活性在个别红细胞。在中度HGPRT缺乏症的家庭，其中半合子的红细胞没有显着标记的这个程序，杂合子显示两个红细胞群体，一个缺乏HGPRT和一个含有HGPRT活性。另一方面，在HGPRT缺乏严重并表现为Lesch-Nyhan综合征的家族中，杂合子仅显示正常的标记模式。因此，嵌合体存在于中度杂合子的红细胞中，但不存在于严重的HGPRT缺乏症。前一个发现支持里昂假说6，而后一个发现表明，携带突变型HGPRT基因的X染色体优先失活，或者X染色体随机失活，随后选择含有突变型HGPRT酶的红细胞前体。
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 hemizygote1,2. 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.