RESUMO
INTRODUCTION: A founder mutation, p.L302P, in sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1), causing Niemann-Pick disease, a recessive lysosomal storage disorder, was reported to be associated with increased risk of Parkinson's disease (PD) in Ashkenazi Jewish population. Several other studies about the association between SMPD1 variants and PD were performed afterward in other populations. However, the results on the role of SMPD1 mutations for PD have been conflicting. This study aimed to investigate the role of mutations in SMPD1 in Chinese PD patients. METHODS: We sequenced all the exons of this gene in 512 Chinese Han cases with sporadic Parkinson's disease and 495 matched healthy control subjects. RESULTS: We identified Leu-Ala (Val) repeat variants and six known single nucleotide variants (p.A36V, p.D212D, p.P332R, p.G508R, p.P533L, p.T544T) in SMPD1 in both patients and normal controls. Case-control analysis showed the association between Leu-Ala (Val) repeat variants in SMPD1and Chinese Han patients with PD (χ2 = 8.771, p = 0.012), and the allele with less than seven LeuAla (Val) repeats may increase the risk of PD (p = 0.010). CONCLUSION: We identified association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with sporadic Parkinson's disease. Our results provide further support for the role of lysosomal pathways in PD development.
Assuntos
Estudos de Associação Genética , Variação Genética/genética , Doença de Parkinson/genética , Esfingomielina Fosfodiesterase/genética , Idoso , Povo Asiático/etnologia , Povo Asiático/genética , Estudos de Casos e Controles , Dipeptídeos/genética , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Encéfalo/metabolismo , Glucose/metabolismo , Proteínas Mitocondriais/genética , Mutação/genética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genética , Fatores de Transcrição/genética , Adulto , Encéfalo/diagnóstico por imagem , Proteínas de Ligação a DNA , Saúde da Família , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de PósitronsRESUMO
Mutations in CHCHD2 gene have been reported in autosomal dominant Parkinson's disease (ADPD). However, there is still lack of evidence supported CHCHD2 mutations lead to ADPD in other populations. We performed whole exome sequencing, positron emission tomography (PET), and haplotype analyses in an ADPD pedigree and then comprehensively screened for CHCHD2 gene mutations in additional 18 familial parkinsonism pedigrees, 364 sporadic PD patients, and 384 healthy controls to assess the frequencies of known and novel rare nonsynonymous CHCHD2 mutations. We identified a heterozygous variant (c.182C>T; p.Thr61Ile) in the CHCHD2 gene in the ADPD pedigree. PET revealed a significant reduction in dopamine transporter binding in the putamen and caudate nucleus of the proband, similar to idiopathic PD. The single nucleotide variant 5C>T (Pro2Leu) in CHCHD2 was confirmed to have a significantly higher frequency among sporadic PD patients than controls. Our results confirm that ADPD can be caused by CHCHD2 mutations and show that the Pro2Leu variant in CHCHD2 may be a risk factor for sporadic PD in Chinese populations.