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A novel polymorphism in SEL1L confers susceptibility to Alzheimer's disease

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A novel polymorphism in SEL1L confers susceptibility to Alzheimer's disease
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  Neuroscience Letters 398 (2006) 53–58 A novel polymorphism in SEL1L confers susceptibilityto Alzheimer’s disease Giuliana Saltini a , Roberto Dominici d , Carlo Lovati b , Monica Cattaneo c ,Stefania Michelini a , Giulia Malferrari a , Andrea Caprera c , Luciano Milanesi c ,Dario Finazzi f  , Pierluigi Bertora b , Elio Scarpini e , Daniela Galimberti e ,Eliana Venturelli e , Massimo Musicco c , Fulvio Adorni c ,Claudio Mariani b , Ida Biunno c , g , ∗ a  Department of Sciences and Biomedical Technologies, University of Milan Via F.lli Cervi 93, 20090 Segrate-Milan, Italy b  Department of Neurology, University of Milan, Ospedale L. Sacco, Via G.B. Grassi 74, I-20157 Milan, Italy c  Institute for Biomedical Technologies (National Research Council), Via F.lli Cervi 93, 20090 Segrate-Milan, Italy d  Lab of Clinical Chemistry, Ospedale L. Sacco, Via G.B. Grassi 74, I-20157 Milan, Italy e  Department of Neurological Sciences, “Dino Ferrari” Center and CEND, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy f  Section of Chemistry, Faculty of Medicine, University of Brescia, Brescia, Italy g  BioRep SrL Via Fantoli 16/15, Milano, Italy Received 14 October 2005; received in revised form 13 December 2005; accepted 14 December 2005 Abstract Alzheimer’s disease (AD) is considered to be a conformational disease arising from the accumulation of misfolded and unfolded proteins in theendoplasmic reticulum (ER). SEL1L is a component of the ER stress degradation system, which serves to remove unfolded proteins by retrogradedegradation using the ubiquitin-proteosome system. In order to identify genetic variations possibly involved in the disease, we analysed the entireSEL1L gene sequence in Italian sporadic AD patients. Here we report on the identification of a new polymorphism within the SEL1L intron 3(IVS3-88 A>G), which contains potential binding sites for transcription factors involved in ER-induced stress. Our statistical analysis shows apossible role of the novel polymorphism as independent susceptibility factor of Alzheimer’s dementia.© 2005 Published by Elsevier Ireland Ltd. Keywords:  Alzheimer’s disease; SEL1L; ER-associated degradation (ERAD); Genetics; Polymorphism Alzheimer’sdisease(AD)isthemostcommonformofdementiaand its incidence is clearly age dependent and doubles every 5years after age 65 [10]. The causes of AD are still unknown butboth environmental factors and heritable predisposition mostlikely contribute to the development of the disease [21,34].Increasing evidences show that protein aggregation have a crit-ical role in AD characterized by extracellular deposition of   -amyloidpeptidesinplaquesandneurofibrillarytangleswithinneurons, being the main neuropathological features of disease[8].Asoftoday,diseasecausingorpredisposingmutationshave ∗ Corresponding author. Present address: ITB-CNR, Via Fratelli Cervi 93,20090 Segrate, Milano, Italy. Tel.: +39 02 26422712; fax: +39 02 26422770.  E-mail address:  ida.biunno@itb.cnr.it (I. Biunno). been unambiguously identified in only four genes: amyloid pre-cursorprotein(APP)[11],presenilin1(PSEN1)[38],presenilin 2[36]andapolipoprotein-E(APOE)[23].Fullypenetrantmuta- tions in APP, PSEN1 and PSEN2 have been associated with therare early onset familial forms of AD [4], whereas the carrier status for the  4 allele of APOE is clearly associated to the mostcommon sporadic forms [7]. Besides the  4 allele, other geneticsusceptibility factors have been proposed: polymorphisms ongenes encoding for   2-macroglobulin,   1-anti-chymotrypsin,angiotensin I converting enzyme, though many studies did notreplicatetheseresults[2,29,35].Astrongerconfirmationisavail-able on the association between AD and a polymorphism inthe interleukin-1 [12,22,30,33] and NOS3 genes [13]. During recent years several analytical strategies with different markershave been applied on different population studies, in addition to 0304-3940/$ – see front matter © 2005 Published by Elsevier Ireland Ltd.doi:10.1016/j.neulet.2005.12.038  54  G. Saltini et al. / Neuroscience Letters 398 (2006) 53–58 full-genomescreensusinglinkageorassociation-basedmethod-ologies;theresultsobtainedrevealedanumberoflocus-specificand AD candidate genes [9]. However, no single study has yet emerged as being reproducible and APOE still remains the onlygeneclearlyassociatedtoAD[3].Accumulatingevidencessug- gest that a high level of endoplasmic reticulum (ER) stress andconsequently defective ER stress signalling can cause chronichuman diseases such as Alzheimer’s and Parkinson’s disease,prion-related encephalopathies, type I and II diabetes [1,4,19].High ER-stress elicits the unfolded protein response (UPR),an adaptive response of the cell. A component of UPR is theER-associateddegradation(ERAD)system[20],whichrequires retrograde transport of unfolded proteins from the ER back tothe cytosol for degradation by the ubiquitin-proteosome system[6,39]. SEL1L is a component of the ERAD system [15,24,41], thus we screened a population of AD patients and matchedcontrolsforgenomicmutationsandherewereportontheidenti-ficationofanewintronicpolymorphismsignificantlyassociatedwith AD dementia.A total of 180 consecutive patients (122 women and 58 men,age range 76.96 ± 7.87 years; mean age years) clinically diag-nosed as AD were enrolled at the Neurology Units of OspedaleMaggiore Policlinico (Milan) and Ospedale L. Sacco (Milan).All patients underwent a standard battery of examinations,including familiarity and medical history, physical and neuro-logical examination, screening laboratory tests, neurocognitiveevaluation, brain magnetic resonance imaging (MRI) or com-puted tomography (CT). Dementia severity was assessed by the Table 1Primer sequences and relative product sizes used for PCR and sequencing reactionsSEL1L region Primer name Primer nucleotide sequence PCR products size (bp)Promoter To11586F 5 ′ -GCTCTTATCACTATGCCCAAT 674IB32R 5 ′ -GCACACAGCAGCAGCGTCAGIB31F 5 ′ -CCAAAGTCCTTCACTTGGC 704PROM6R 5 ′ -GTGCGGGTGACTGTTGAAGTIB11R 5 ′ -GACCCGCATCCTCCTCTCGGExon 1 PROM5F 5 ′ -GACCATGGTGATTGGACCAGA 379SEL1LProEx01R 5 ′ -GACAGCCCAGTGCGAGATExon 2 SEL1LEx02F 5 ′ -CTAAACCCCCAACCCATTTT 323SEL1LEx02R 5 ′ -CAGACCTCATATCCTTTCTAAExon 3 SEL1LEx03F 5 ′ -GTAAAAATAACGGTCAAATAGG 393SEL1LEx03R 5 ′ -CAGTCTTCTTCAGCCTCTTTExon 4 SEL1LEx04F 5 ′ -CAGGCATCATGAATCTTTGC 369SEL1LEx04R 5 ′ -TGTGGAAAAAGGATGGCTAGExon 5 SEL1LEx05F 5 ′ -CATTTTGTTTGTATGACTGCC 303SEL1LEx05R 5 ′ -CTTCTGCGTCTCTGGCAGExon 6 SEL1LEx06F 5 ′ -AGGAAATTATTTATGTTGCGTTT 389SEL1LEx06R 5 ′ -ATGGTCAGCCACAAAATTGGExon 7+8 SEL1LEx0708F 5 ′ -TGTCTGTCTGTGTCTGTCTT 349SEL1LEx0708R 5 ′ -GAAAAAGTTGTGGCCGCTATExon 9 SEL1LEx09F 5 ′ -TTTGTTCCACGAAGAATGACA 267SEL1LEx09R 5 ′ -TGAGTCCACATAAAAGAGCCExon 10 SEL1LEx10F 5 ′ -GCAGCTGGAATTGTACTTCT 345SEL1LEx10R 5 ′ -GCTCAGGGCAATGAAAATGTExon 11 SEL1LEx11F 5 ′ -CAGAAGCCATTTTACGACCA 280SEL1LEx11R 5 ′ -GCTCATTTGTGATGGGTGTTExon 12 SEL1LEx12F 5 ′ -TTTGGCTGAAAGTCAAAAGCA 292SEL1LEx12R 5 ′ -GAAAATGCCTCAGAACAGCAExon 13 SEL1LEx13F 5 ′ -GTAATTGGAGAGAGGGTTAC 266SEL1LEx13R 5 ′ -CATGAATCATACTTAATATGCAGExon 14 SEL1LEx14F 5 ′ -GTCTGATGAGAAGAAGAAAGT 302SEL1LEx14R 5 ′ -GGCTGACTGGAAGCTAATTAExon 15 SEL1LEx15F 5 ′ -TCCCCCTATGACTTAATGTAT 364SEL1LEx15R 5 ′ -CAGAATTTGATAGCACCCATTExon 16 SEL1LEx16F 5 ′ -ACTCAGTAAGAATTCTTTCATTA 373SEL1LEx16R 5 ′ -TAGGCTGAGTCTAGAACTACExon 17 SEL1LEx17F 5 ′ -AGCTGCCAGAAATTGAAGGA 416SEL1LEx17R 5 ′ -CCTGTGTGTTCAGTTCCAGExon 18 SEL1LEx18F 5 ′ -AACTTATGCTTCACCTATCCT 264SEL1LEx18R 5 ′ -AGTACTCGGCTTCATGATTTAExon 19 SEL1LEx19F 5 ′ -AGCATGTCAATGGGAGGAG 368SEL1LEx19R 5 ′ -GTGGCCTGAAATCCAACTGExon 20 SEL1LEx20F 5 ′ -GTTTAGGTGAGGGAAACTCA 364SEL1LEx20R 5 ′ -TACCTGCAGGACCACTCTTExon 21 SEL1LEx21F 5 ′ -TCTGTACTTACTTCTGGTGAT 517SEL1LEx21R 5 ′ -CATATGGCACTGAAACAAACA  G. Saltini et al. / Neuroscience Letters 398 (2006) 53–58  55 Clinical Dementia Rating (CDR) and the Mini Mental ScaleExamination (MMSE) at the time of sampling. The diagnosis of probable AD was made according to NINCDS-ADRDA criteria[27].A total of 153 ethnicity-matched healthy individuals (94women and 59 men, mean age 66.8 ± 11.93 years) were alsoenrolled by the previously mentioned hospitals. Healthy con-trol cases (HC) were selected from a non-demented populationhaving a normal score at the Mini Mental State Examination(score>24). An informed consent was obtained from all sub- jects enrolled in the study. A database was created, hosted at theInstitute of Biomedical Technologies of the CNR, Segrate (MI)andcontainsclinicalandbio-moleculardatadirectlyinsertedbyinvestigators involved in the project, to support statistical stud-ies, and collects patients’ data while maintaining their completeanonymity. Whole blood samples were stored at  − 20 ◦ C untilused for DNA extraction and genomic DNA was purified usinga silica-based method previously described [25].SEL1L (AF052059) promoter region ( − 1190 to start codon)and exons (including exon–intron junctions) were amplifiedby standard PCR. The primer sequences and relative prod-uct sizes are listed in Table 1. PCR reactions were carriedout using the DYnaZYme DNA Polymerase (Finnzymes) withstandard amplification conditions; the PCR products were puri-fied using ExoSAP treatment (GE Healthcare), according tothe manufacturer’s instructions, and sequenced with the DYE-namic ET Dye Terminator Cycle Sequencing Kit (GE Health-care). Sequence products were purified using Montage SEQ96SequencingReactionCleanupKIT(Millipore).AllPCR,purifi-cation and sequencing reactions were prepared using the Multi-probeIIHTEXRoboticLiquidHandlingSystem(PerkinElmer)[26]. All sequences were performed on the MegaBACE 1000DNA Analysis System (GE Healthcare). Cimarron 3.12 wasused as the base caller. The strength of association betweenAlzheimer’sdiseaseandtheallelicconfigurationforSEL1Lwasquantified with the odds ratio and its statistical significance wascalculated with chi-square as described by Manthel–Haenszel.The estimates of the risk were also calculated adjusting forthe presence of the APOE   4 allele by means of a logisticregression analysis. For each risk estimate the 95% confidenceinterval was derived from the standard errors of the regressioncoefficients.DNA sequencing of the SEL1L gene (minimal promoter,exons and exon–intron junctions) was initially performed on24 AD Italian patients. Sequence analysis of PCR amplifiedgenomic DNA revealed a novel polymorphism located in theintron located between exons 3 and 4: here the adenine (A)at position  − 88 from intron/exon junction is substituted by aguanine (G) residue (IVS3-88A>G). Table 2 describes the sta-tisticalanalysisperformedinourcase–controlassociationstudyon a total of 180 patients diagnosed as having sporadic ADpatients and 153 healthy controls. The novel intronic polymor-phism was observed in hetero- and homozygosis with differentfrequency in each group of subjects. AD patients analysed wereolder than controls but equally distributed in the two sexes.   4allele of APOE was more common among cases both in heteroand homozygosis. Also A/G and G/G SEL1L polymorphismswere more common in Alzheimer disease cases than in con-trols. When the strength of association was quantified with thecalculation of odds ratios as estimates of the relative risk, a sig-nificant risk increase was observed for age, number of   4 allelesand for the A/G or G/G polymorphism. The crude estimates of AD risk were more than five folds increased in subjects present-ing one or two   4 alleles and were about 1.9 times increasedin subjects with the A/G or G/G polymorphism with respect tothose with the A/A configuration. When the multivariable anal-ysis was carried out age was still significant, the risk associatedwith   4 allele was about six times increased in those subjectswith one allele and more than nine times increased in those withtwo  4alleles.Theriskincreaseassociatedwith  4werestatisti-cally significant. The risk associated with the polymorphisms of SEL1Lwasstatisticallysignificant(  p =0.045)withanORof1.8for carriers of one or two G alleles when compared to subjectswithout G alleles. Table 3 describes the genotype frequencies Table 2Demographic characteristics, number of    4 alleles and SEL1L polymorphisms in patients with Alzheimer disease and controlsControls Alzheimer’s disease Crude odds ratio 95% CI Multivariable odds ratio 95% CIGenderMen 59 (38,8) 58 (32,2)Women 93 (61,2) 122 (67,8) 1.3 (0.8–2.1),  p =0.211 1.2 (0.7–2.1),  p =0.577Mean age (range) 66.8 (18,0–93,0) 76.9 (52,0–93,0) 1.1 (1.07–1.13),  p =0.000 1.1 (1.1–1.12),  p =0.000Number of    4 alleles0 133 (86,9) 98 (54,4)1 18 (11,8) 74 (41,1) 5.6 (3.1–9.9),  p =0.000 5.8 (2.8–11.8),  p =0.0002 2 (1,3) 8 (4,4) 5.4 (1.1–26.1),  p =0.035 9.7 (1.2–81.4),  p =0.036SEL1L polymorphismA/A 116 (75,8) 114 (63,3)A/G or G/G 37 (24,2) 66 (36,7) 1.9 (1.2–3.0),  p =0.010 1.8 (1.0–3.3),  p =0.045Total 153 180Odds ratios are presented crude and adjusted for all the other variables of the table. Numbers in parentheses are column percentages when not otherwise specified.CI 95% stands for confidence interval at 95%.  56  G. Saltini et al. / Neuroscience Letters 398 (2006) 53–58 Table 3Genotype frequencies and raw  p -values for AA, AG and GG comparisonsGenotype frequencies TotalAD ControlsSeL1L Pol-88 A/A 114(63,3) 116(75,8) 230A/G 58(32,2) 30(19,6) 88G/G 8(4,4) 7(4,6) 15Total 180 153 333  p =0.033 (chi-square test). Number in parenthesis are percentages and the  p -value is calculated using the chi-square test. for the A and G comparisons showing a statistically significantassociation (  p =0.033).The accumulation of proteins in neurons seems to be influ-enced by the ERAD system [17,18] which plays an importantfunctioninthesurvivalofstressedcells[15].TheERADsystem serves to remove unfolded proteins by retrograde degradationusing the ubiquitin-proteosome system [6,39]. Components of  the ERAD system are HRD1 and SEL1L; HRD1 is a bona fidehomologoftheyeastHrd1[14]andSEL1Lacandidatehomologof the yeast Hrd3 [32]. Both HRD1 and SEL1L co-localize in the endoplasmic reticulum, physically interact to each other andare induced in response to UPR [14,19,24]. SEL1L forms a 1:1 complex with HRD1 and together links dislocation, ubiq-uitination and extraction of misfolded proteins from the ERmembrane [24]. We focused our attention on the gene SEL1L due to its sub-cellular location and induced expression uponER stress (Cattaneo, personal communication) with the aim tofind sequence alterations which could be associated to AD. Weperformed mutation scanning of the entire gene (intron/exonboundaries included) and the minimal promoter on an Italianpopulation of AD patients as well as controls and found a pre-viously undetected polymorphism (IVS3-88A>G). The risk of AD associated with this polymorphism is statistically signifi-canteventhoughthecontrolpopulationanalysedwassomewhatyounger than the patients, but equally distributed by gender.When multivariate analysis was carried out, age was still signif-icant and the risk associated with   4 allele was about six timesincreased in those subjects with one allele and more than ninetimes in those with two   4 alleles. The risk increase associatedwith   4 was statistically significant.To our knowledge, this is the first report on a study of ADpatients and controls using a gene known to play a function intheresponseofcellstoERstress.Thepolymorphismlieswithinthe longest intron of the gene in which, extensive computer-aidedanalysis(MatInspectorprogram),revealedthepresenceof consensus sequences for transcription factors known to be acti-vated in ER stress (Table 4). Although no similarity to knowntranscription factor consensus sequences were found neitherin subjects with A nor with the G transition genotype, sev-eral eukaryotic regulatory elements were identified within thislarge intronic region. In particular we found the presence of several potential binding sites for transcription factors that areinvolvedinER-inducedstresssuchas:HSF-1,ATF6andCHOP[37,40,43], among them, the heat shock factor 1 which is thefirst factor responsible for the transcriptional response to heatstress in mammalian cells [31]. The heat shock response pro- tects proteins from the deleterious effects of acute or chronicstress by stabilizing and refolding protein-folding intermediatesor facilitating protein degradation, a central issue to neurode-generative diseases. It was reported that activation of HSF-1 ishighly sensitive to oxidative stress, a condition associated withneurodegenerative disorders and that its DNA binding activityis lower in AD than control cybrids [5]. The CHOP protein,also known as growth arrest and DNA damage-inducible gene Table 4Consensus sequences for transcription factors within the SEL 1L intron 3Transcription factor Position a Core sim b Matrix sim c Sequence d Heat shock factor 1820–830 1.000 0.977 AGAAtattctc1667–1677 1.000 0.987 AGAAtgttctt2627–2637 1.000 0.970 AGAAttttctc5298–5308 1.000 0.966 AGAAttttcct9876–9886 1.000 0.952 AGAAgcttcca12240–12250 1.000 0.935 AGAAaaatcgg14605–14615 1.000 0.950 AGAAacttccaHeterodimers of CHOP and C/EBP alpha1891–1903 1.000 0.907 gagTGCAatggca9036–9048 1.000 0.976 agaTGCAatagcc9434–9446 1.000 0.918 accTGCAatacacMember of b-zip family induced by ER damage/stress binds to theERSE in association with NF-Y7222–7236 1.000 0.946 ctgCCACtccccttt18118–18132 1.000 0.936 ctgCCACacccagctActivating transcription factor 6 member of b-zip family, inducedby ER stress5702–5722 1.000 0.878 atcataaGACGtgagcggggt10525–10545 1.000 0.987 gggtgatGACGtgagctggcg12802–12822 1.000 0.893 cttgggcGACGtgacttcgag a The coordinates refer to the beginning of the third intron. b Core similarity: the core sequence of a matrix is defined as the (usually four) consecutive highest conserved positions of the matrix. The maximum core similarityof 1.000 is only reached when the highest conserved bases of a matrix match exactly in the sequence. c Matrix similarity: a perfect match to the matrix gets a score of 1.000, a good match to the matrix usually has a similarity of >0.8. d Base pairs in capital letters describe the core sequence used by MatInspctor. Underlined base pairs show a high information content, i.e. the matrix exhibits ahigh conservation (ci-value>60) at this position.  G. Saltini et al. / Neuroscience Letters 398 (2006) 53–58  57 153 (GADD153), is a leucine zipper transcription factor that isactivated in response to induced ER stress [42]. It was reported that the basal protein levels of CHOP are markedly increasedby PS1 mutations which are responsible for early onset familialAlzheimer’s disease by a mechanism believed to involve per-turbed endoplasmic reticulum function and altered proteolyticprocessing of the amyloid precursor protein [28]. The activating transcription factor 6 (ATF6) is a basic leucine zipper transcrip-tion factor that during ER stress binds to DNA on the ER stressresponse element (ERSE) in association with NF-Y and acti-vates the unfolded protein response target genes [43]. It wasreportedthatSEL1LisinducedbyERstressviathesignaltrans-ducersATF6andIRE1[15].Moreover,thefamilialAlzheimer’s disease-linkedpresenilin-1mutationleadstovulnerabilitytoERstressbyinhibitingtheactivationofERstresstransducersATF6,IRE1 and PERK [16].We hypothesize, based on the reported observations, that theG substitution may cause a marked change in the secondarystructure of DNA, thus affecting the access of the transcriptionapparatus and possibly down regulating SEL1L signalling andtheERADresponse.Infact,thepresenceofGconfigurationmayformamorepotentialpalindrome,thermodynamicallymoresta-ble, which may interfere with protein/DNA interaction leadingto SEL1L down-modulation.In conclusion, here we describe a novel polymorphism in theSEL1LgenewhichcouldbeariskfactorinADdevelopment.Sofar, association studies with candidate genes have been widelyused for the study of complex diseases, however, this approachhasbeencriticizedbecauseresultsaresometimesnotreplicated.Therefore, further association studies, using larger populationstogetherwithfunctionalanalysisareindeednecessarytoconfirmand reproduce these preliminary data. 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