Categories: Lysosomal storage disease

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 601015 (gene) , 607625 (trait)

Links to MONDO diseases:

• MONDO:0011873: Niemann-Pick disease, type C2

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

Molecular basis: Zampieri et al. (2014): "intronic mutation located 5 nt downstream of the canonical donor splice site of exon 1"; c.82+5G>A; "the mutation affects the splicing process causing the retention of 105 bp of intron 1 in the mature mRNA, which would lead to the in frame insertion of 35 amino acids between residues 28 and 29 of the NPC2 protein (p.G28_S29ins35)." Rakib et al. (2023): "studied the molecular basis of Siamese and Japanese domestic (JD) cats that were previously diagnosed with NP [Yamagami et al. 1989; Kamiya et al. 1991a; Kamiya et al. 1991b; Morozumi and Uchida 1998 ]. ... a missense mutation (NPC2:c.376G>A, p.V126M) was identified as a candidate pathogenic mutation in both types of cats. ... The Siamese cat was homozygous and the JD cat was heterozygous for this mutation. No other exonic NPC2 mutations were detected in the JD cat; however, a homozygous splice variant (c.364-4C>T) was identified, which is not known to be associated with this disease."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Zampieri et al. (2014) reported two kittens from the same litter "with tremors at the age of 3 months, which progressed to dystonia and severe ataxia. At 6 months of age cat 2 was unable to stand without assistance and had bilaterally reduced menace response. It died at the age of 10 months. ... At 9 months cat 1 was unable to walk, developed seizures and it was euthanized at 21 months."

Pathology: Zampieri et al. (2014): "histological analysis of the brain showed the presence of neurons with cytoplasmic swelling and vacuoles, gliosis of the substantia nigra and degeneration of the white matter. Spheroids with accumulation of ubiquitinated aggregates were prominent in the cerebellar cortex. Purkinje cells were markedly reduced in number and they showed prominent intracytoplasmic storage. Scattered perivascular aggregates of lymphocytes and microglial cells proliferation were present in the thalamus and midbrain. Proliferation of Bergmann glia was also observed. In the liver, hepatocytes were swollen because of accumulation of small vacuoles and foamy Kupffer cells were also detected. Foamy macrophages were observed within the pulmonary interstitium and alveoli as well. ... Filipin staining of cultured fibroblasts showed massive storage of unesterified cholesterol."

Breeds: Japanese domestic, Siamese (Cat) (VBO_0100221).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: