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Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson's disease.

ABSTRACT: Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2657 PD patients and 3647 controls from 3 cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the 3 cohorts. To examine their association with PD, regression models adjusted for age, sex, and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.

SUBMITTER: Ouled Amar Bencheikh B

PROVIDER: S-EPMC7302975 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson's disease.

Ouled Amar Bencheikh Bouchra B Senkevich Konstantin K Rudakou Uladzislau U Yu Eric E Mufti Kheireddin K Ruskey Jennifer A JA Asayesh Farnaz F Laurent Sandra B SB Spiegelman Dan D Fahn Stanley S Waters Cheryl C Monchi Oury O Dauvilliers Yves Y Espay Alberto J AJ Dupré Nicolas N Greenbaum Lior L Hassin-Baer Sharon S Rouleau Guy A GA Alcalay Roy N RN Fon Edward A EA Gan-Or Ziv Z

Neurobiology of aging 20200408

Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performe ...[more]

PMID: 32371106

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Project description:BackgroundIt has been reported that oxidation product of cholesterol, 7-ketocholesterol, increases in plasma of patients with NP-C. Previously, we established a rapid test to determine the plasma 7-ketocholesterol level and found it elevated significantly in patients with acid sphingomyelinase deficient NPD and NP-C disease.MethodsIndividuals randomly referred to our outpatient clinics in the past two years for hepatosplenomegaly or isolated splenomegaly, who have been excluded as acid sphingomyelinase deficient NPD or Gaucher disease, and individuals with newborn cholestasis, psychomotor regression/retardation, were screened for plasma 7-ketocholesterol level. Individuals with high 7-ketocholesterol level were then analyzed for NPC1 and NPC2 gene mutation to confirm the accuracy of NP-C diagnosis.ResultsBy screening the plasma 7-ketocholesterol of suspect individuals, 12 out of 302 (4%) had shown remarkable high levels compared with reference. All these twelve individuals were subsequently confirmed to be NP-C by DNA analysis of NPC1 and NPC2 genes, with the early infantile form (n = 7), the late infantile form (n = 1), the juvenile form (n = 1) and the adult form (n = 1). Furthermore, two NP-C patients without observable neuropsychiatric disability were picked up through this procedure. Only one patient had NP-C due to NPC2 gene mutations, with the rest due to NPC1 gene mutations. We found that in NP-C patients AST was usually mildly elevated and ALT was in a normal range when jaundice was not present. In total, 22 mutant alleles were identified in the NPC1 gene, including six novel small deletions/insertions, e.g., c.416_417insC, c.1030delT, c.1800delC, c.2230_2231delGT, c.2302_2303insG, and c.2795dupA; seven novel exonic point mutations, c.1502A>T (p.D501V), c.1553G>A (p.R518Q), c.1832A>G (p.D611G), c.2054T>C (p.I685T), c.2128C>T(p.Q710X), c.2177G>C (p.R726T), c.2366G>A (p.R789H), and one novel intronic mutation c.2912-3C>G. Small deletions/insertions constituted nearly half of the mutant alleles (10/22, 45%), indicating a unique mutation spectrum in this cohort of Chinese NP-C patients.ConclusionOur data confirm in a clinical setting that screening plasma 7-ketocholesterol is an efficient and practical diagnostic tool to identify NP-C patients from suspect individuals. Patients without neuropsychological involvement could also be identified by this method therefore allowing an opportunity for earlier treatment.

Dataset Information

Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson's disease.

Publications

Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson's disease.

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