WormBase Tree Display for Disease_model_annotation: WBDOannot00000480
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| WBDOannot00000480 | Disease_term | DOID:14504 | |||
|---|---|---|---|---|---|
| Disease_of_species | Homo sapiens | ||||
| Modeled_by | Genotype | WBGenotype00000003 | |||
| Asserted_gene | WBGene00003561 | ||||
| WBGene00003562 | |||||
| Association_type | is_model_of | ||||
| Evidence_code | GO_code | IMP | |||
| ECO_term | ECO:0007013 | ||||
| Genetic_sex | hermaphrodite | ||||
| Paper_evidence | WBPaper00004161 | ||||
| Disease_model_description | Mutations in the human genes NPC1 and NPC2 are implicated in Niemann-Pick disease, type C and type C2(NPC and NPC2); this disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration, including ataxia, spasticity, seizures, and loss of speech; at the cellular level NPC is characterized by cholesterol accumulation in lysosomes and aberrant feedback regulation of cellular cholesterol homeostasis, as normally NPC1 may function as a transmembrane efflux pump; the two orthologs of NPC1 in elegans, ncr-1 and ncr-2 contain sterol-sensing domains; C. elegans is a sterol-auxotroph, requiring cholesterol in the growth medium; the elegans model for NPC disease consists of the ncr-1;ncr-2 double mutant which shows hypersensitivity to cholesterol deprivation and dies in the first larval stage, it also shows a constitutive dauer formation phenotype, a third-stage larval form that exists under stress; the inappropriate dauer formation phenotype has revealed a function for both ncr-1 and ncr-2 in sterol-derived hormone synthesis (dauer-regulating sterol hormone), upstream of the daf-9(cytochrome P450 enzyme) and daf-12 (nuclear hormone receptor) pathway; further, studies show that human intestinal cholesterol transporter, NPC1L1, identified as the target for the drug ezetimibe (Zetia), a cholesterol absorption inhibitor, and human NPC1 can functionally substitute for C. elegans ncr-1 and ncr-2; the findings in such animal models are important for an understanding of NPC protein function, synthesising cholesterol is energetically demanding, and therefore, the storage of cholesterol in NPC-affected neurons has strong implications for the understanding of the cholesterol budget in neuronal tissue; restoring cholesterol synthesis in neurons may be a route to alleviating NPC symptoms resulting from insufficiency, if cholesterol unavailability is a primary cellular consequence of NPC deficit. | ||||
| DB_info | Database | OMIM | gene | OMIM:607623 | |
| disease | OMIM:257220 | ||||
| Curator_confirmed | WBPerson324 | ||||
| Date_last_updated | 13 Feb 2018 00:00:00 |
