Table 2.
Niemann-Pick mutations in the phosphoesterase domain of ASM
| Mutation | N-P type | Character of mutation | Model interpretation | Reference |
| L302P | A | Homozygous; no measurable ASM activity in patients. Lack of activity confirmed by mutagenesis studies. May result in misfolded protein. | Not in the proximity of the dimetal center in the hydrophobic core. Predicted to result in a kink in the helix or loop where it resides and possibly result in an unstable protein. | Levran et al. 1992 |
| H319Y | A | Homozygous; lethal at 1 year | His319 is predicted to be directly involved in substrate hydrolysis. Mutation of this residue is predicted to significantly reduce the Kcat of ASM. | Sikora et al. 2003 |
| P371S | B | Homozygous; mild disease | Not in the proximity of the dimetal center. Appears to be solvent-exposed and may affect subdomain orientation, resulting in decreased catalytic efficiency of ASM. | Sikora et al. 2003 |
| M382I | A | Heterozygous; no residual ASM activity seen in mutagenesis studies | Located in the loop containing the NX3CX3N motif predicted to be involved in SM recognition | Takahashi et al. 1992 |
| N383S | B | Heterozygous; no residual ASM activity seen in mutagenesis studies | Located in the loop containing the NX3CX3N motif predicted to be involved in SM recognition | Takahashi et al. 1992 |
| W391G | B | Homozygous; slow SM degradation rates; results in an unstable protein | Predicted to sit in a hydrophobic pocket that contains residues from the NX3CX3N motif. Mutation may destabilize ASM by disrupting important hydrophobic interactions | Sperl et al. 1994; Ferlinz et al. 1995 |
| H421Y | B | Homozygous; childhood death, predicted to sit in putative catalytic site and possibly interact with zinc | Not in the proximity of the dimetal center or the zinc ions. Sits between two central beta sheets. Predictions of mutation cannot be made due to limitations of the model. | Simonaro et al. 2002 |