GENETIC-HETEROGENEITY IN NIEMANN-PICK-C-DISEASE - A STUDY USING SOMATIC-CELL HYBRIDIZATION AND LINKAGE ANALYSIS

The primary molecular defect underlying Niemann-Pick C disease (NPC) i s still unknown. A wide spectrum of clinical and biochemical phenotype s has previously been documented. Indication of genetic heterogeneity has recently been provided for one patient. In the present study, soma tic cell hybridization experiments were carried out on skin fibroblast cultures from 32 unrelated NPC patients covering the range of known c linical and biochemical phenotypes. The criterion for complementation was the restoration of a normal intracellular fluorescent pattern in p olykaryons stained with filipin to document cholesterol distribution. Crosses between the various cell lines revealed a major complementatio n group comprising 27 unrelated patients and a second minor group comp rising 5 patients. Linkage analysis in one multiplex family belonging to the minor complementation group showed that the mutated gene does n ot map to the 18q11-12 region assigned to the major gene. Patients in the first group spanned the whole spectrum of clinical and cellular ph enotypes. No consistent clinical or biochemical phenotype was associat ed with the second complementation group. Three of the five group 2 pa tients, however, presented with a new rare phenotype associated with s evere pulmonary involvement leading to death within the first year of life. No biochemical abnormality specific of either group could be dem onstrated with regard to tissue lipid storage pattern, intralysosomal cholesterol storage, and regulation of cholesterol homeostasis. Mutati ons affecting at least two different genes have thus been shown to und erlie NPC. The two gene products may function together or sequentially in a common metabolic pathway affecting intracellular cholesterol tra nsport.