Mutational analysis of PRNP in Alzheimer’s disease and frontotemporal dementia in China

The prion protein (PRNP) gene is associated with prion diseases, whereas variants of the PRNP gene may also explain some cases of Alzheimer disease (AD) and frontotemporal dementia (FTD) in Caucasian populations. To determine the prevalence of the PRNP gene in patients with AD and FTD in China, we screened all exons of the PRNP gene in a cohort of 683 cases (606 AD and 77 FTD) in the Chinese Han population and we detected a novel missense mutation p.S17G in a late-onset AD (LOAD) patient. Furthermore, we analyzed the PRNP M/V polymorphism at codon 129, which was previously reported as a risk factor. However, there were no significant differences in genotype and allele frequency either in AD (OR = 0.75[0.378–1.49], P = 0.492), or FTD patients (OR = 2.046[0.265–15.783], P = 0.707). To our knowledge, this is the first study to reveal a correlation between the PRNP gene and Chinese AD and FTD patients in a large cohort. This study reports a novel p.S17G mutation in a clinically diagnosed LOAD patient, suggesting that the PRNP mutation is present in Chinese AD patients, whereas, M129V polymorphism is not a risk factor for AD or FTD in the Chinese Han population.

[1]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[2]  S V Faraone,et al.  Genetics of Alzheimer's disease. , 1996, Journal of the Formosan Medical Association = Taiwan yi zhi.

[3]  B. Ghetti,et al.  Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Freedman,et al.  Frontotemporal lobar degeneration , 1998, Neurology.

[5]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[6]  B. Dubois,et al.  Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. , 1999, American journal of human genetics.

[7]  Ű. Langel,et al.  Cell membrane translocation of the N-terminal (1-28) part of the prion protein. , 2002, Biochemical and biophysical research communications.

[8]  K. Sakai,et al.  A patient with dementia with Lewy bodies and codon 232 mutation of PRNP , 2002, Neurology.

[9]  T. Asada,et al.  Absence of association between codon 129/219 polymorphisms of the prion protein gene and Alzheimer's disease in Japan , 2003, Annals of neurology.

[10]  A. Hofman,et al.  PRNP Val129 homozygosity increases risk for early‐onset Alzheimer's disease , 2003, Annals of neurology.

[11]  A. Pestronk,et al.  Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein , 2004, Nature Genetics.

[12]  H. Reichmann,et al.  Analysis of the polymorphic prion protein gene codon 129 in idiopathic Parkinson’s disease , 2006, Journal of Neural Transmission.

[13]  G. Schellenberg,et al.  Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia , 2005, Annals of neurology.

[14]  L. Fratiglioni,et al.  Role of genes and environments for explaining Alzheimer disease. , 2006, Archives of general psychiatry.

[15]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[16]  J. Mortimer,et al.  Early-Life Risk Factors for Alzheimer Disease , 2006, Alzheimer disease and associated disorders.

[17]  R. Carp,et al.  Polymorphisms at codons 129 and 219 of the prion protein gene (PRNP) are not associated with sporadic Alzheimer's disease in the Korean population , 2007, European journal of neurology.

[18]  S. Sorbi,et al.  Codon 129 polymorphism of prion protein gene in sporadic Alzheimer’s disease , 2008, European journal of neurology.

[19]  H. Kretzschmar,et al.  Novel PRNP mutation in a patient with a slow progressive dementia syndrome. , 2008, Medical science monitor : international medical journal of experimental and clinical research.

[20]  F. Tagliavini,et al.  Atypical frontotemporal dementia as a new clinical phenotype of Gerstmann-Straussler-Scheinker disease with the PrP-P102L mutation. Description of a previously unreported Italian family , 2008, Neurological Sciences.

[21]  Nick C Fox,et al.  The heritability and genetics of frontotemporal lobar degeneration , 2009, Neurology.

[22]  A. Singleton,et al.  A Case of Dementia With PRNP D178Ncis-129M and No Insomnia , 2009, Alzheimer disease and associated disorders.

[23]  R. Tanzi,et al.  The Genetics of Alzheimer Disease: Back to the Future , 2010, Neuron.

[24]  K. Sleegers,et al.  Genetic contribution of FUS to frontotemporal lobar degeneration , 2010, Neurology.

[25]  G. Schellenberg,et al.  Familial prion disease with alzheimer disease‐like tau pathology and clinical phenotype , 2011, Annals of neurology.

[26]  P. Johannsen,et al.  Frontotemporal Dementia Caused by CHMP2B Mutations , 2011, Current Alzheimer research.

[27]  V. V. Van Deerlin,et al.  Prion Protein Codon 129 Polymorphism Modifies Age at Onset of Frontotemporal Dementia With the C.709-1G>A Progranulin Mutation , 2011, Alzheimer disease and associated disorders.

[28]  S. Ramón y. Cajal,et al.  A novel mutation I215V in the PRNP gene associated with Creutzfeldt–Jakob and Alzheimer’s diseases in three patients with divergent clinical phenotypes , 2012, Journal of Neurology.

[29]  V. Meininger,et al.  C9orf72 hexanucleotide repeat expansions as the causative mutation for chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia. , 2012, Archives of neurology.

[30]  Xinglong Wang,et al.  Cellular prion protein is essential for oligomeric amyloid-β-induced neuronal cell death. , 2012, Human molecular genetics.

[31]  E. Génin,et al.  A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. , 2014, Brain : a journal of neurology.

[32]  C. Cupidi,et al.  Novel N-terminal domain mutation in prion protein detected in 2 patients diagnosed with frontotemporal lobar degeneration syndrome , 2014, Neurobiology of Aging.

[33]  L. Schöls,et al.  Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease , 2014, Neurobiology of Aging.

[34]  J. Hardy,et al.  A nonsense mutation in PRNP associated with clinical Alzheimer's disease , 2014, Neurobiology of Aging.

[35]  B. Tang,et al.  Mutational analysis in early-onset familial Alzheimer's disease in Mainland China , 2014, Neurobiology of Aging.

[36]  P. Panegyres,et al.  The Patterns of Inheritance in Early-Onset Dementia , 2015, American journal of Alzheimer's disease and other dementias.

[37]  D. Mari,et al.  PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population. , 2016, Journal of Alzheimer's disease : JAD.

[38]  B. Tang,et al.  Analyses MAPT, GRN, and C9orf72 mutations in Chinese patients with frontotemporal dementia , 2016, Neurobiology of Aging.

[39]  C. Broeckhoven,et al.  Molecular genetics of early-onset Alzheimer's disease revisited , 2016, Alzheimer's & Dementia.