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[Advances in molecular genetics of the Niemann-Pick group of diseases].

Recent advances in molecular genetics of the Niemann-Pick group of diseases are reviewed. Types A and B Niemann-Pick disease are characterized by a deficiency of one of lysosomal hydrolases, i.e. acid sphingomyelinase. The enzyme was partially purified from a large amount of urine and the cDNA clones, encoding acid sphingomyelinase, were cloned. The gene encoding the enzyme has been localized at the region p 15.1-p 15.4 of chromosome 11 by analysis of a somatic cell hybrid and in situ hybridization. Several mutations, causing deficient sphingomyelinase activity, were identified among patients with different ethnic backgrounds. The expression experiments revealed that the mutations responsible for type A cause no detectable residual enzyme activities, while mutations responsible for type B, cause relatively higher residual enzyme activity of 2% to 40 %. Biochemical abnormalities in Type C Niemann-Pick fibroblasts are characterized by normal acid sphingomyelinase activity, accumulation of intracellular cholesterol and defective esterification of exogenously added cholesterol. The basic defect is still unknown. Similar abnormalities were observed in mutant mouse strains, BALB/c and C57 BL/Ks. The mutant C57BL/Ks mouse, which was found in Japan, has been characterized as a sphingomyelinosis and the genetic locus, spm, has been assigned to chromosome 18. By transferring a single human chromosome to the immortalized cell line, we have found human chromosome 18 can reduce intracellular cholesterol accumulation. More recently, Pentchev and co-workers found linkage of type C to human chromosome 18. It is highly probable that the spm and human type C mutations involve the same gene. Molecular cloning of the defective gene in muman and mouse mutation become practically possible.