Genetic heterogeneity in Niemann-Pick C disease: A study using somatic cell hybridization and linkage analysis

Journal Article · Mon Jan 01 04:00:00 EST 1996 · American Journal of Human Genetics

OSTI ID:232379

Vanier, M T ^[1]; Rodriguez-Lafrasse, C ^[1]; Duthel, S ^[2]

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1. Lyon-Sud School of Medicine, Oullins (France)
2. Centre Hospitalier Lyon-Sud, Pierre Benite (France); and others

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 phenotype 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. 31 refs., 4 figs., 2 tabs.

• OSTI ID: 232379
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: 1 Vol. 58; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
CHOLESTEROL
GENE MUTATIONS
GENES
GENETIC MAPPING
HEREDITARY DISEASES
HUMAN CHROMOSOME 18
HYBRIDIZATION
LYSOSOMES
METABOLIC DISEASES
PATIENTS
PHENOTYPE
RECESSIVE MUTATIONS
SOMATIC CELLS
STATISTICS
STORAGE