Smpd1, which encodes sphingomyelin phosphodiesterase (ASM), is crucial as its product acid sphingomyelinase is involved in lipid metabolism. Deficient activity of ASM due to Smpd1 mutations is associated with Niemann-Pick Types A and B (NPA/B) diseases, autosomal recessive lysosomal storage disorders [1,4,5,6,7].

Mutations in Smpd1 are also associated with other diseases. In Parkinson's disease, certain Smpd1 mutations like p.L302P or p.fsP330 in the Ashkenazi Jewish cohort, and p.A487V in the Montreal/Montpellier cohort, were associated with the disease. Reduced acid-sphingomyelinase activity was linked to an earlier onset of PD. Also, Smpd1 knockout and knockdown led to increased α-synuclein levels in cells [3]. In β-thalassemia major patients, the Smpd1 gene c.132_143del, p.A46_L49del variant was detected, with associated differences in plasma chitotriosidase, ferritin, liver enzymes, and leukocyte acid sphingomyelinase levels [2].

In summary, Smpd1 is essential for normal lipid metabolism through the activity of acid sphingomyelinase it encodes. Its mutations are associated with Niemann-Pick Types A and B, Parkinson's disease, and β-thalassemia major. Research on Smpd1, including knockout/knockdown models, has provided insights into the role of Smpd1 in these disease conditions, helping to understand the underlying mechanisms and potentially guiding diagnosis and treatment [1-6].

References:

1. Zampieri, Stefania, Filocamo, Mirella, Pianta, Annalisa, Bembi, Bruno, Dardis, Andrea. 2015. SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. In Human mutation, 37, 139-47. doi:10.1002/humu.22923. https://pubmed.ncbi.nlm.nih.gov/26499107/

2. Dursun, Fadime Ersoy, Özen, Filiz. 2023. SMPD1 gene variants in patients with β-Thalassemia major. In Molecular biology reports, 50, 3355-3363. doi:10.1007/s11033-023-08275-x. https://pubmed.ncbi.nlm.nih.gov/36725747/

3. Alcalay, Roy N, Mallett, Victoria, Vanderperre, Benoît, Rouleau, Guy A, Gan-Or, Ziv. 2019. SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. In Movement disorders : official journal of the Movement Disorder Society, 34, 526-535. doi:10.1002/mds.27642. https://pubmed.ncbi.nlm.nih.gov/30788890/

4. Wang, Ruisong, Qin, Ziyi, Huang, Long, Yang, Pinhong, Shi, Tieliu. 2023. SMPD1 expression profile and mutation landscape help decipher genotype-phenotype association and precision diagnosis for acid sphingomyelinase deficiency. In Hereditas, 160, 11. doi:10.1186/s41065-023-00272-1. https://pubmed.ncbi.nlm.nih.gov/36907956/

5. Schuchman, Edward H, Desnick, Robert J. 2016. Types A and B Niemann-Pick disease. In Molecular genetics and metabolism, 120, 27-33. doi:10.1016/j.ymgme.2016.12.008. https://pubmed.ncbi.nlm.nih.gov/28164782/

6. Molnar, Maria Judit, Szlepak, Tamas, Csürke, Ildikó, Erdős, Melinda, Dezsőfi, Antal. 2023. Case report: The spectrum of SMPD1 pathogenic variants in Hungary. In Frontiers in genetics, 14, 1158108. doi:10.3389/fgene.2023.1158108. https://pubmed.ncbi.nlm.nih.gov/37347058/

7. Pfrieger, Frank W. 2023. The Niemann-Pick type diseases - A synopsis of inborn errors in sphingolipid and cholesterol metabolism. In Progress in lipid research, 90, 101225. doi:10.1016/j.plipres.2023.101225. https://pubmed.ncbi.nlm.nih.gov/37003582/