Six novel NPC1 mutations in Chinese patients with Niemann–Pick disease type C

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 76; no. 4; pp. 592 - 595
• Main Authors: Yang, C-C, Su, Y-N, Chiou, P-C, Fietz, M J, Yu, C-L, Hwu, W-L, Lee, M-J
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.04.2005; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; Alzheimer's disease; Apoptosis; Asian Continental Ancestry Group - genetics; Ataxia; Atrophy; Biological and medical sciences; Biopsy, Needle; Bone marrow; Bone Marrow - pathology; Brain - pathology; Carrier Proteins - genetics; Child; Child, Preschool; China; Chinese; Cholesterol; Chromosomes, Human, Pair 18 - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; denaturing high performance liquid chromatography; DHPLC; DNA Mutational Analysis; Exons - genetics; Female; Fibroblasts; Humans; Magnetic Resonance Imaging; Male; Medical sciences; Membrane Glycoproteins - genetics; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Mutation; Mutation, Missense; mutations; Neurology; Neurons - pathology; Niemann-Pick Diseases - ethnology; Niemann-Pick Diseases - genetics; Niemann–Pick disease type C; Niemann–Pick type C; novel; NPC; NPC1 gene; Point Mutation - genetics; Polymerase Chain Reaction; Proteins; Short Report; Sterols; Taiwan; China; Taiwan; Human; Nervous system diseases; Central nervous system disease; Metabolic diseases; Chinese; Lipids; Niemann Pick disease; Mutation; Enzymopathy; Lipoidosis; Cerebral disorder; Genetic disease
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.2004.046045

In patients with Niemann–Pick disease type C (NPC), an autosomal recessive lipid storage disorder, neurodegeneration can occur in early life. Vertical ophthalmoplegia and extrapyramidal signs may be seen. Cholestatic jaundice and hepatosplenomegaly occur frequently in patients with early onset disease, with bone marrow biopsies showing diffuse infiltration of foamy histiocytes. Cholesterol esterification in skin fibroblasts is reduced, resulting in intracellular accumulation of cholesterol. NPC1 mutations are responsible for the disease in ∼95% of patients. NPC1 encodes a 1278 amino acid protein which contains 13 transmembrane domains. Over 130 mutations have been identified in NPC1, with over a third present within an NPC1 specific cysteine-rich domain positioned in a large extracellular loop. It has been proposed that the defect in cholesterol homoeostasis is the cause of neuronal apoptosis, but the precise role of the NPC1 protein and the functional implications of its mutations remain unknown. Although NPC is routinely diagnosed by biochemical analysis, identification of molecular defects helps confirm the diagnosis and enables family studies, and rapid, accurate prenatal diagnosis. This report describe the analysis of the NPC1 gene in five Taiwanese/Chinese patients with NPC. Six novel NPC1 mutations (N968S, G1015V, G1034R, V1212L, S738Stop, and I635fs) were identified of which three are missense mutations located in the cysteine-rich domain. These are the first NPC1 mutations reported from Chinese patients with NPC.