This report describes Niemann-Pick disease, type C1 (NPC1), which is a subtype of Niemann-Pick disease; NPC1 is inherited as an autosomal recessive. The human gene implicated in this disease is NPC1, which encodes an intracellular cholesterol transporter between endosomes and lysosomes; NPC2 acts in the same process. There are two genes in flies orthologous to human NPC1, Dmel\Npc1a and Dmel\Npc1b; classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both Drosophila genes. A second similar gene in human, NPC1L1, has not been implicated in Niemann-Pick disease.
The human NPC1 gene has not been introduced into flies.
Homozygous loss-of-function mutations in either Dmel\Npc1a or Dmel\Npc1b result in lethality at larval or pupal stages; Npc1a larvae exhibit aberrant subcellular sterol accumulation. Dmel\Npc1a mutants been characterized as adults, using dietary supplementation or expression of a GAL4-UAS copy in the ring gland to overcome lethality. Resulting adults exhibit progressive locomotor defects, shortened life spans, and multiple other indications of neurological abnormalities.
Variants implicated in human disease have been introduced into flies, but have not been characterized. Variant(s) implicated in human disease (analogous mutation in fly gene): V890M in the fly Npc1a gene (corresponds to V889M in the human NPC1 gene); A1015T in the fly Npc1a gene (corresponds to A1017T in the human NPC1 gene); I1060T in the fly Npc1a gene (corresponds to I1061T in the human NPC1 gene)
[updated Feb. 2020 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 C1; NPC1](https://omim.org/entry/257220)
[NPC INTRACELLULAR CHOLESTEROL TRANSPORTER 1; NPC1](https://omim.org/entry/607623)
Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration and a highly variable clinical phenotype. Patients with the 'classic' childhood onset type C usually appear normal for 1 or 2 years with symptoms appearing between 2 and 4 years. They gradually develop neurologic abnormalities which are initially manifested by ataxia, grand mal seizures, and loss of previously learned speech. Spasticity is striking and seizures, particularly myoclonic jerks, are common. In the childhood-onset form, death usually occurs at age 5 to 15; adult-onset forms, with slower progression, have also been reported [from MIM:257220; 2016.09.09]
Niemann-Pick disease type C1 is caused by homozygous or compound heterozygous mutation in the NPC1 gene. Approximately 95% of cases of Niemann-Pick type C are caused by mutations in the NPC1 gene. [from MIM:257220; 2016.09.09]
Niemann-Pick disease type C (NPC) is characterized by defective transport of cholesterol and other lipids inside of cells. Excessive amounts of cholesterol accumulate within the liver and spleen and excessive amounts of other lipids accumulate in the brain (http://nnpdf.org/the-disease/overview/).
NPC1 (NPC intracellular cholesterol transporter 1) encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain; acts with NPC2. [from Gene Cards, NPC1; 2016.09.09]
Many to many: 2 human to 2 Drosophila. The additional human gene is NPC1L1.
