Vanier M T, Duthel S, Rodriguez-Lafrasse C, Pentchev P, Carstea E D
Department of Biochemistry, INSERM-CNRS 189, Lyon-Sud School of Medicine, Oullins, France.
Am J Hum Genet. 1996 Jan;58(1):118-25.
The primary molecular defect underlying Niemann-Pick C disease (NPC) is still unknown. A wide spectrum of clinical and biochemical phenotypes has previously been documented. Indication of genetic heterogeneity has recently been provided for one patient. In the present study, somatic cell hybridization experiments were carried out on skin fibroblast cultures from 32 unrelated NPC patients covering the range of known clinical and biochemical phenotypes. The criterion for complementation was the restoration of a normal intracellular fluorescent pattern in polykaryons stained with filipin to document cholesterol distribution. Crosses between the various cell lines revealed a major complementation group comprising 27 unrelated patients and a second minor group comprising 5 patients. Linkage analysis in one multiplex family belonging to the minor complementation group showed that the mutated gene does not map to the 18q11-12 region assigned to the major gene. Patients in the first group spanned the whole spectrum of clinical and cellular phenotypes. No consistent clinical or biochemical phenotypes was associated with the second complementation group. Three of the five group 2 patients, however, presented with a new rare phenotype associated with severe pulmonary involvement leading to death within the first year of life. No biochemical abnormality specific of either group could be demonstrated with regard to tissue lipid storage pattern, intralysosomal cholesterol storage, and regulation of cholesterol homeostasis. Mutations affecting at least two different genes have thus been shown to underlie NPC. The two gene products may function together or sequentially in a common metabolic pathway affecting intracellular cholesterol transport.
尼曼-皮克C病（NPC）潜在的主要分子缺陷仍不清楚。此前已记录了广泛的临床和生化表型。最近有一名患者显示出遗传异质性迹象。在本研究中，对来自32名无亲缘关系的NPC患者的皮肤成纤维细胞培养物进行了体细胞杂交实验，这些患者涵盖了已知的临床和生化表型范围。互补的标准是在用制霉菌素染色的多核体中恢复正常的细胞内荧光模式，以记录胆固醇分布。不同细胞系之间的杂交显示出一个主要互补组，包含27名无亲缘关系的患者，以及一个次要互补组，包含5名患者。对属于次要互补组的一个多人家庭进行的连锁分析表明，突变基因并不定位于分配给主要基因的18q11 - 12区域。第一组患者涵盖了整个临床和细胞表型范围。第二互补组未发现一致的临床或生化表型。然而，五名第二组患者中有三名表现出一种新的罕见表型，伴有严重的肺部受累，导致在生命的第一年内死亡。关于组织脂质储存模式、溶酶体内胆固醇储存以及胆固醇稳态调节，两组均未显示出特定的生化异常。因此，已证明至少两个不同基因的突变是NPC的基础。这两种基因产物可能在影响细胞内胆固醇转运的共同代谢途径中共同发挥作用或依次发挥作用。
