Mueller O T, Honey N K, Little L E, Miller A L, Shows T B
J Clin Invest. 1983 Sep;72(3):1016-23. doi: 10.1172/JCI111025.
The genetic relationships between the multiple variants of mucolipidosis II (I-cell disease) and mucolipidosis III (pseudo-Hurler polydystrophy) were investigated with a sensitive genetic complementation analysis procedure. These clinically distinct disorders have defects in the synthesis of a recognition marker necessary for the intracellular transport of acid hydrolases into lysosomes. Both disorders are associated with an inherited deficiency of a uridine diphosphate-N-acetyl-glucosamine: lysosomal enzyme precursor N-acetyl-glucosamine-phosphate transferase activity. We had previously shown that both disorders are genetically heterogeneous. Complementation analysis between mucolipidosis II and III fibroblasts indicated an identity of mucolipidosis II with one of the three mucolipidosis III complementation groups (ML IIIA), suggesting a close genetic relationship between these groups. The presence of several instances of complementation within this group suggested an intragenic complementation mechanism. Genetic complementation in heterokaryons resulted in increases in N-acetyl-glucosamine-phosphate transferase activity, as well as in the correction of lysosomal enzyme transport. This resulted in increases in the intracellular levels of several lysosomal enzymes and in the correction of the abnormal electrophoretic mobility pattern of intracellular beta-hexosaminidase. The findings demonstrate that a high degree of genetic heterogeneity exists within these disorders. N-acetyl-glucosamine-phosphate transferase is apparently a multicomponent enzyme with a key role in the biosynthesis and targeting of lysosomal enzymes.
运用一种灵敏的基因互补分析方法，研究了黏脂贮积症II型（I型细胞病）和黏脂贮积症III型（假胡勒氏多营养不良症）多种变异型之间的遗传关系。这些临床症状不同的疾病，在酸性水解酶向溶酶体进行细胞内转运所需的识别标记合成方面存在缺陷。两种疾病均与尿苷二磷酸-N-乙酰葡糖胺：溶酶体酶前体N-乙酰葡糖胺磷酸转移酶活性的遗传性缺乏有关。我们之前已表明这两种疾病在遗传上具有异质性。黏脂贮积症II型和III型成纤维细胞之间的互补分析表明，黏脂贮积症II型与三种黏脂贮积症III型互补组之一（ML IIIA）相同，提示这些组之间存在密切的遗传关系。该组内存在多个互补实例，提示存在基因内互补机制。异核体中的基因互补导致N-乙酰葡糖胺磷酸转移酶活性增加，以及溶酶体酶转运的纠正。这导致几种溶酶体酶的细胞内水平增加，并纠正了细胞内β-己糖胺酶异常的电泳迁移模式。这些发现表明，这些疾病存在高度的遗传异质性。N-乙酰葡糖胺磷酸转移酶显然是一种多组分酶，在溶酶体酶的生物合成和靶向中起关键作用。
