This report describes a model of Niemann-Pick disease, type A and B (NPD-A, NPD-B), also known as sphingomyelinase deficiency. Niemann-Pick disease type A and B are subtypes of Niemann-Pick disease and are frequently described as a single entity with a clinical spectrum; both exhibit autosomal recessive inheritance. The gene implicated in both diseases is SMPD1, which encodes a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. In Drosophila, there is a single high-scoring ortholog, Dmel\Asm, for which an amorphic allele created by targeted recombination, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There are two additional orthologs of SMPD1 in Drosophila, CG15534 and CG15533.
The human SMPD1 gene has not been introduced into flies.
A variant implicated in human disease introduced (as analogous mutation in fly gene): R571L in the fly Dmel\Asm, gene (corresponds to R498L in the human SMPD1 gene) has been introduced into flies. See the 'Disease-Implicated Variants' table below. A variant analogous to a disease-implicated mutation in the human SMPD1 gene has also been introduced into Dmel\CG7049 by homologous recombination; however, it has not yet been characterized.
Loss of function alleles of Dmel\Asm are lethal before adulthood, and exhibit defects in gas-filling of trachea. This gas-filling defect is also observed in tracheal-specific RNAi-mediated knockdown of Dmel\Asm. Flies bearing the Dmel\AsmR571L mutation also exhibit a tracheal gas-filling defect.
[updated Jan. 2025 by FlyBase; FBrf0222196]
Multiple types of Niemann-Pick disease include the classic infantile form (type A; MIM:257200), the visceral form (type B; MIM:607616), and the subacute or juvenile form (type C; MIM:257220 and MIM:607625). [from MIM:257220; 2016.09.09]
Niemann-Pick disease comprises a group of lipid metabolism and lysosomal storage diseases with a wide range of symptoms and variable severity. Abnormal lipid metabolism causes a buildup of harmful amounts of lipids in various organs, primarily the liver, spleen, brain, and bone marrow. Affected organs, symptoms, and treatments vary based on the specific sub-type. However, every type is severe and can shorten a person's life expectancy. [http://www.healthline.com/health/niemann-pick-disease; 2016.09.26]
[NIEMANN-PICK DISEASE, TYPE A](https://omim.org/entry/257200)
[SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1](https://omim.org/entry/607608)
Niemann-Pick disease types A and B are caused by an inherited deficiency of acid sphingomyelinase activity. The clinical phenotype ranges from a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age (type A, MIM:257200) to a later-onset nonneurologic form (type B, MIM:607616) that is compatible with survival into adulthood. Since intermediate cases also have been reported, the disease is best regarded a single entity with a clinical spectrum (summary by Schuchman, 2007; pubmed:17632693). [from MIM:257200 and MIM:607616; 2019.11.02]
Niemann-Pick disease type A is caused by homozygous or compound heterozygous mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1). [from MIM:257200; 2019.11.02]
SMPD1 encodes a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide; it also has phospholipase C activity. [Gene Cards, SMPD1; 2019.11.02]
Acid sphingomyelinase is a lipid hydrolase that cleaves the cell membrane sphingolipid sphingomyelin into ceramide. Ceramide has a key role as a lipid mediator that participates in regulation of cell death and survival (Taniguchi and Okazaki, 2014; pubmed:24355909).
One to many: 1 human to 3 Drosophila.
High-scoring ortholog of human SMPD1; other low-scoring orthologs of SMPD1 in fly (3 Drosophila to 1 human). Dmel\CG3376 shares 37% identity and 53% similarity with the human gene.
