Disease relevance of SMPD1

• The deficient activity of SMPD1 is the enzymatic defect in Types A and B Niemann-Pick disease [1].
• Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer [2].
• The data identify the acid sphingomyelinase and ceramide as key molecules for the infection of human cells with rhinoviruses [3].
• Acid sphingomyelinase activation requires caspase-8 but not p53 nor reactive oxygen species during Fas-induced apoptosis in human glioma cells [4].
• In FAP adenoma tissue, alkaline sphingomyelinase activity was reduced by 90% compared to controls (P < 0.0001), acid sphingomyelinase by 66% (P < 0.01) and neutral sphingomyelinase by 54% (P < 0.05) [5].

Psychiatry related information on SMPD1

• Among 183 depressed patients participating in a randomized long-term treatment trial of fluoxetine and nortriptyline, 30 patients had borderline personality disorder (BPD), 53 had other personality disorders (OPD), and 100 had no personality disorders (NPD) [6].
• Acid sphingomyelinase (A-SMase) and its reaction product ceramide may play a role in the pathophysiology of depressive disorders and in the therapeutic action of antidepressive drugs [7].
• The considerable similarity of the clinical and paraclinical signs and of the effects of anti-epileptic treatments do not seem to justify the individualization of different subgroups as a function of the EEG patterns: the NPD are always the result of focal epilepsy, and never of a pathology of movement or of parasomnia [8].
• MATERIAL AND METHODS: In the present investigation early non-depressed PD patients (NPD), early PD patients with mild depressive symptoms (DPD), patients with primary depression (DEP) and healthy controls (HC) completed a range of neuropsychological tests [9].
• This result, with hepatomegaly, mental retardation, feeding problems, a failure to thrive and muscle-hypotony, partially resembled the ASM-deficient forms of Niemann-Pick disease (NPD) [10].

High impact information on SMPD1

• Complementation of ASM-deficient fibroblasts from Niemann-Pick disease patients restored N. gonorrhoeae-induced signaling and entry processes [11].
• The activation of PC-PLC and ASM, therefore, is an essential requirement for the entry of N. gonorrhoeae into distinct nonphagocytic human cell types including several epithelial cells and primary fibroblasts [11].
• Ceramide inhibition of PI(3)K is dependent on acid-sphingomyelinase [12].
• Types A and B Niemann-Pick disease both result from the deficient activity of the lysosomal hydrolase, acid sphingomyelinase (E.C. 3.1.4.12) [13].
• Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients [13].

Chemical compound and disease context of SMPD1

• Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes [14].
• Using cultured skin fibroblasts from I-cell disease patients, in which one of the enzymes responsible for mannose phosphorylation, GlcNAc-phosphotransferase, is deficient, we determined ASM activities in cell homogenates and media [15].
• In the present study, we show that the anticancer drug cisplatin induces clustering of CD95 at the surface of the human colon cancer cell line HT29, an event inhibited by the inhibitor of acid sphingomyelinase (aSMase) imipramine [16].
• The biosynthesis of acid sphingomyelinase in normal and I-cell disease fibroblasts was investigated by metabolic labeling with [35S]methionine and immunoprecipitation followed by polyacrylamide gel electrophoresis and fluorography [17].
• In C6 glioma cells, W-7 and not H-7 inhibited dose-dependently acid sphingomyelinase, a result indicating the modulation of this lysosomal enzyme by a calmodulin-dependent system [18].

Biological context of SMPD1

• In contrast to the previous provisional localization to chromosome 17, these results assign a single locus for human SMPD1 to 11p15.1----p15.4 [1].
• Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1) [19].
• In a panel of 15 hybrid cell lines, amplification of the human SMPD1 sequence was 100% concordant with the presence of human chromosome 11 [1].
• The G29fsX74, S248R, H319Y, P371S, F463S, P475L and Y537H SMPD1 mutations are all novel and were verified by PCR/RFLP and/or ARMS [20].
• We identified nine novel mutations in the SMPD1 gene including six single base changes c.2T>G, c.96G>A, c.308T>C, c.674T>C, c.732G>C, c.841G>A (p.M1_W32del, p.W32X, p.L103P, p.L225P, p.W244C, p.A281T) and three frameshift mutations c.100delC, c.565dupC, c.575dupC (p.G34fsX42, p.P189fsX1 and p.P192fsX14) [21].

Anatomical context of SMPD1

• Oligonucleotide primers were synthesized to PCR amplify the human, but not murine, SMPD1 sequences in man-mouse somatic cell hybrids [1].
• The observation that UV-C light also induced CER generation and the externalization of acid sphingomyelinase and JNK in human platelets conclusively rules out the involvement of a nuclear signal generated by DNA damage in the initiation of a UV light response, which is generated at the plasma membrane [22].
• It is demonstrated here that UV-C light irradiation of U937 cells results in the activation and translocation of a Zn2+-independent acid sphingomyelinase, leading to CER accumulation in raft microdomains [22].
• Acid sphingomyelinase was ubiquitously distributed in all rat tissues examined, highest in liver and lowest in adipose tissue [23].
• Treatment of NPD cell lines with 5-aza-2'-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated [24].

Associations of SMPD1 with chemical compounds

• In the present study, using inhibitors of ceramide synthase (fumonisin B1), ketosphinganine synthetase (L-cycloserine), acid sphingomyelinase (D609 and desipramine) and neutral sphingomyelinase (GW4869), the role of ceramide in X-ray-induced apoptosis was investigated in MOLT-4 cells [25].
• Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol [26].
• A three-base deletion was identified of nucleotides 1821-1823 in the cDNA which predicted the removal of an arginine residue from position 608 of the acid sphingomyelinase polypeptide (delta R608) [13].
• Activation of human acid sphingomyelinase through modification or deletion of C-terminal cysteine [27].
• Acid ceramidase but not acid sphingomyelinase is required for tumor necrosis factor-{alpha}-induced PGE2 production [28].

Physical interactions of SMPD1

• Purpose: We determined whether LPS-induced TLR4 assembly and activation are dependent on the sphingolipid metabolite ceramide, produced by acid sphingomyelinase following the initial binding of LPS to CD14 [29].

Regulatory relationships of SMPD1

• In contrast, although acid sphingomyelinase was also stimulated by TNF-alpha, its inhibition was without effect [30].
• NSMase and aSMase are activated by different cytoplasmic domains of the 55 kDa TNF-receptor and are coupled to select pathways of TNF signaling [31].
• Here, we show that CEACAM receptor-mediated phagocytosis of Opa(52)-expressing N. gonorrhoeae into human cells results in a rapid activation of the acid sphingomyelinase [32].

Other interactions of SMPD1

• UV-C light induces raft-associated acid sphingomyelinase and JNK activation and translocation independently on a nuclear signal [22].
• In contrast, activation of signaling enzymes that are linked to the "death domain" of TR55, like acid sphingomyelinase and c-Jun-N-terminal protein kinase as well as TNF signaling of apoptosis in U937 and L929 cells, are blocked in the presence of MDC [33].
• Activation of acid sphingomyelinase by interleukin-1 (IL-1) requires the IL-1 receptor accessory protein [34].
• CD161 (human NKR-P1A) signaling in NK cells involves the activation of acid sphingomyelinase [35].
• Exogenous C16-ceramide (20 microM) and acid sphingomyelinase induced trophoblast apoptosis, an effect abrogated completely by cotreatment with 10 ng/ml EGF [36].

Analytical, diagnostic and therapeutic context of SMPD1

• 4. To provide an independent regional gene assignment, in situ hybridization was performed using the radiolabeled human SMPD1 cDNA [1].
• Given the difficult management of the disease, we opted for a preventive approach to the suffering families by screening the whole SMPD1 gene for mutations followed by Preimplantation Genetic Diagnosis (PGD) [37].
• There was no chromosomal alteration found by conventional karyotyping of the patient s lymphocytes.BWS-associated genes as well as the human ASM gene (SMPD1) are all located at 11p15 [10].
• We found that ATRA induced the 4-fold elevation of acid sphingomyelinase (ASMase) activity 24 h after treatment in NB4 cells, but not in NB4/RA cells [38].
• Functional characterization of the N-glycosylation sites of human acid sphingomyelinase by site-directed mutagenesis [39].

References