Smpd1, which encodes sphingomyelin phosphodiesterase (ASM), is crucial as its deficiency leads to Niemann-Pick Types A and B (NPA/B), autosomal recessive lysosomal storage disorders [1,4,5,6,7]. ASM is involved in sphingolipid metabolism, hydrolyzing sphingomyelin to ceramide, a key lipid messenger that impacts cell signaling, apoptosis, and membrane dynamics [1,5,6].

Mutations in Smpd1 have diverse clinical implications. In NPA/B patients, disease-causing variants are evenly distributed along the gene, with missense (65.4%) and frameshift (19%) mutations being most common, and p.R610del is frequently reported globally and associated with an attenuated NP disease type B phenotype [1]. Smpd1 gene c.132_143del, p.A46_L49del variant in β-thalassemia major patients is related to higher plasma chitotriosidase, ferritin, and liver enzyme levels, and lower leukocyte acid sphingomyelinase levels [2]. In Parkinson's disease, Smpd1 mutations are associated with the disease in the Ashkenazi Jewish cohort, and reduced acid-sphingomyelinase activity is linked to an earlier onset. Smpd1 knockout and knockdown result in increased α-synuclein levels in certain cells [3]. In acid sphingomyelinase deficiency (ASMD), severe Smpd1 mutations like deletion and insertion can cause type A, while mild missense mutations often lead to type B [4].

In conclusion, Smpd1 is essential for normal sphingolipid metabolism. Studies on Smpd1-related mutations through various genetic models (although not specifically KO/CKO mouse models in the provided references) have revealed its role in diseases such as Niemann-Pick Types A and B, β-thalassemia major, and Parkinson's disease, providing insights into genotype-phenotype correlations and disease mechanisms.