Acid sphingomyelinase gene and diagnosis of Niemann-pick disease

Abstract

The present invention relates to the acid sphingomyelinase gene and to methods of diagnosing Niemann-Pick disease. It is based, at least in part, on the cloning and expression of the full-length cDNA encoding acid sphingomyelinase and on the discovery of mutations in the acid sphingomyelinase gene of Ashkenazi Jewish Niemann-Pick disease patients.

Description

1. INTRODUCTION[0001] The present invention relates to the acid sphingomyelinase gene and to methods of diagnosing Niemann-Pick disease. It is based, at least in part, on the cloning and expression of the full-length cDNA encoding acid sphingomyelinase, the cloning and characterization of the genomic structure of the acid sphingomyelinase gene, and on the discovery of a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish Niemann-Pick disease patients.2. BACKGROUND OF THE INVENTION[0002] Types A and B Niemann-Pick disease (NPD) are autosomal recessive disorders resulting from the deficient activity of the lysosomal hydrolase, acid sphingomyelinase (ASM; sphingomyelin cholinephosphohydrolase, E:C 3.1.3.12) and the accumulation of sphingomyelin, primarily in reticuloendothelial lysosomes (Niemann, 1914, Fahrb. Kinderheikd, 79:1-6; Brady et al., 1966, Proc. Natl. Acad. Sci. U.S.A. 55;366-369; Fredrickson, 1966, in "The Metabolic Basis of Inherited Disease; S...

AI Technical Summary

Problems solved by technology

Although patients with both subtypes have residual ASM activity (about 1 to 10% of normal), biochemical analysis cannot reliably distinguish the two phenotypes.

Moreover, the clinical course of Type B NPD is highly variable, and it is not presently possible to correlate disease severity with the level of residual ASM activity.

Although the enzymatic diagnosis of affected patients with either type A or B NPD can be made reliably (Spence and Callahan, supra), the enzymatic detection of obligate heterozygotes has proven problematic, particularly using peripheral leukocytes as the enzyme source.

Presumably, the occurrence of neutral sphingomyelinases in some sources and / or the presence of residual ASM activity resulting from the mutant allele have contributed to the inability to reliably discriminate carriers for either disease subtype.

Even the: use of cultured skin fibroblasts, which do not express the neutral sphingomyelinase, has not provided unambiguous results with obligate heterozygotes.

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