A novel polymorphism in the human acid sphingomyelinase gene due to size variation of the signal peptide region.

Acid sphingomyelinase (ASM) is the lysosomal enzyme required to hydrolyze sphingomyelin into ceramide and phosphocholine. In man, a deficiency of this enzymatic activity leads to Types A and B Niemann-Pick disease (NPD), a panethnic disease with a relatively high incidence among Ashkenazi Jewish individuals. Analysis of the ASM cDNA and genomic sequences revealed a unique hexanucleotide sequence, CTGG(TC)(GT), located within the signal peptide region of the ASM polypeptide (corresponding to the hydrophobic amino acid sequence LVLALALALALA). Notably, five hexanucleotide repeat units were found in the full-length cDNA, while the genomic sequence contained six, suggesting that this region of the ASM gene may be polymorphic. PCR primers were designed to amplify the repeat region and over 700 normal and NPD ASM alleles were analyzed among Ashkenazi Jewish and non-Jewish populations. Five alleles were identified corresponding to nine, seven, six, five and four hexanucleotide repeats, respectively. The allele frequencies were similar among Jewish and non-Jewish populations and no differences were found among normal individuals and Type A and B NPD patients. Thus, it does not appear to be a common cause of NPD. This intriguing repeat polymorphism should be extremely useful to researchers interested in gene identification and characterization of the chromosomal region 11p15.1-p15.4, as well as individuals interested in the biology of this important lysosomal hydrolase.