SMPD1 Gene-Chromosome 11The SMPD1 gene is responsible for making the enzyme acid sphingomyelinase, which converts sphingomyelin into ceramide. Isoforms 2 and 3 of SMPD have lost catalytic activity. SMPD1 localizes in the lysosomes of cells [1]. Mutations in the SMPD1 gene causes Niemann-Pick disease. This gene is located on the short arm of chromosome 11 and contains six exons [2]. Within the acid sphingomyelinase sequence, three zinc binding sites have been identified [3]. This gene is paternally imprinted, which means that it is only expressed from the maternal chromosome. Therefore if the father has the gene, it will not affect the offspring.
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Over 100 different mutations have been found to cause Niemann-Pick, the majority of which are missense mutations. These mutations change an amino acid to a different amino acid. Two common mutations are the changing of Asparagine to Serine at 383, and Methionine to Isoleucine at 382. These mutations result in acid sphingomyelinase protein that lacks catalytic activity [4].
Exon/Codon2/312
4/427 6/522 6/525 6/577 |
Amino Acid SubstitutionValine to Methionine
Histidine to Arginine Asparagine to Serine Glutamine to Histidine Histidine to Arginine |
The table to the left lists five mutations that were found in Desnick et al. to cause Niemann-Pick type B. These were all missense mutations, resulting in a different amino acid being produced [5]. |
DNA Sequence |
mRNA Sequence |
References
[1] http://www.uniprot.org/uniprot/P17405
[2] http://ghr.nlm.nih.gov/gene/SMPD1
[3] Jones, I., He, X., Katouzian, F., Darroch, P., & Schuchman, E. (2008). Characterization of Common SMPD1 Mutations Causing Types A & B Niemann-Pick Disease and Generation of Mutation-Specific Mouse Models. Molecular Genetics and Metabolism, 95(3), 152. doi: 10.1016/j.ymgme.2008.08.004
[4] Seto, M., Whitlow, M., McCarrick, M., Srinivasan, S., Zhu, Y., Pagila, R., Mintzer, R., Light, D., Johns, A., & Meurer-Ogden, J. (2004). A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase. Protein Science, 13(12), 3172. doi: 10.1110/ps.04966204
[5] Desnick, J., Kim, J., He, X., Wasserstein, M., Simonaro, C., & Schuchman, E. (2010). Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease. Molecular Medicine, 16(7-8), 316. doi: 10.2119/molmed.2010.00017
[1] http://www.uniprot.org/uniprot/P17405
[2] http://ghr.nlm.nih.gov/gene/SMPD1
[3] Jones, I., He, X., Katouzian, F., Darroch, P., & Schuchman, E. (2008). Characterization of Common SMPD1 Mutations Causing Types A & B Niemann-Pick Disease and Generation of Mutation-Specific Mouse Models. Molecular Genetics and Metabolism, 95(3), 152. doi: 10.1016/j.ymgme.2008.08.004
[4] Seto, M., Whitlow, M., McCarrick, M., Srinivasan, S., Zhu, Y., Pagila, R., Mintzer, R., Light, D., Johns, A., & Meurer-Ogden, J. (2004). A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase. Protein Science, 13(12), 3172. doi: 10.1110/ps.04966204
[5] Desnick, J., Kim, J., He, X., Wasserstein, M., Simonaro, C., & Schuchman, E. (2010). Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease. Molecular Medicine, 16(7-8), 316. doi: 10.2119/molmed.2010.00017