A New Mutation Of PSEN1 Gene Loci In Pedigree Analysis Of Clinical Features Of Alzheimer’s Disease

BackgroundAlzheimer ’s disease(AD)is a common neurodegenerative disease with multiple factors and high genetic heterogeneity.The clinical manifestation is multi domain cognitive impairment and Abnormal mental behavior.Alzheimer’s disease has obvious genetic tendency,especially familial AD(FAD).PSEN1,PSEN2,APP and ApoE genes are the four major pathogenic genes of AD.PSEN1、 PSEN2 and APP genes are closely related to FAD.The PSEN1 gene is the most common.At present,AD gene data are mainly abroad,and domestic researches are few.Research shows that there is a distinct distribution of racial differences.We collected clinical data and blood samples from a EOFAD family for genetic testing,which can explore possible mutations associated with AD in this family.PurposeStudy on PSEN1 gene mutation locis and clinical featuresof familial Alzheimer’s disease Methods1.32 family members of the four generation in the FAD family were collected,and30 members of the peripheral blood samples were collected(two of them were deceased).The proband and other patients have been diagnosed by AD.First,we use two generation high-throughput sequencing of proband AD gene.The presenilin 1 gene,presenilin 2 gene,amyloid precursor protein,microtubule associated protein,tau gene,glucocerebrosidase gene 、 valosin protein gene and Clu gene were detected.We use DNA direct sequencing(Sanger sequencing)technology to verify the proband.2.Comparison and analysis of 100 normal people by Sanger sequencing.Consult AD&FTD mutation database(dementia database),PUBMED,China HowNet,Wanfang database and other databases to comparison analysis.3.The conservatism of the location of the mutant loci was compared to the related loci of the NCBI gene pool.4.The Jpred4 software and Swiss comparative modeling method were applied to predict the two or three level structure and function online software of the protein,andto know whether the amino acid structure of the new mutation site changed or related pathogenicity.5.The clinical and neuroimaging evaluation of the precursor was performed,including 3.0T cranial nuclear magnetic resonance multiple sequence analysis and 18 fluorodeoxyglucose PET imaging.The history,past history,surgical trauma history,allergy history and medication history of the members of FAD family were collected and analyzed.Physical examination and neurological examination were performed in detail.Results1.High throughput sequencing and detection of Sanger after sequencing indicated that the proband and 2 other family members have PSEN1 gene exon fourth c.313T>C heterozygous missense mutation,phenylalanine induced by mutation of codon 313 rd encoding for leucine,which leads to p.F105 L mutations.2.Amino acid software predicts that the mutant site is highly likely to be a pathogenic mutation: multiple conservation sequences analysis the mutant amino acid site in a highly conserved region.The Jpred4 and Swiss comparative modeling methods indicate that the two or three level structure and function of protein and amino acids predict that the side chain structure of the 313 rd amino acid encoded by PSEN 1 gene is changed.3.The proband is characterized by progressive memory loss,cognitive dysfunction,accompanied by tinnitus like cicadas,before the onset of a clear history of headache.The MRI in the head suggests atrophy of the left temporal lobe and mild atrophy of the hippocampus.PET-CT suggested that the metabolism of the temporal,parietal and partial frontal lobes decreased and the brain atrophy.Conclusions1.The discovery of the new mutation site p.F105 L of the PSEN1 gene may be associated with the pathogenesis of FAD.2.P.F105 L mutation is reported in China for the first time.3.The cognitive dysfunction associated with tinnitus may be like cicadas phenotype of new p.F105 L mutation.