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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-140399 IOS Press
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Short Communication
Previously Unrecognized Missense Mutation E126K of PSEN2 Segregates with Early Onset Alzheimer’s Disease in a Family
or P
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Ulrich M¨ullera,∗ , Pia Wintera , Claus Bolenderb and Dagmar Noltea
6
a Institute
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b Gemeinschaftspraxis,
8
Handling Associate Editor: Luisa Benussi
dA
uth
of Human Genetics, Justus Liebig University, Giessen, Germany Schl¨uchtern, Germany
Accepted 25 March 2014
14
Keywords: Alzheimer’s disease, early onset Alzheimer disease, E126K PSEN2 mutation, familial segregation, PSEN2
15
INTRODUCTION
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Early onset Alzheimer’s disease (EOAD) with an age of onset A) in PSEN2 in an EOAD patient and her likewise affected mother. This change results in the exchange of amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). Pathogenicity of the mutation is shown by segregation with disease, evolutionary conservation of E126, and in silico analysis of the mutation.
9 10
∗ Correspondence
to: Prof. Dr. med. U. M¨uller, Institut f¨ur Humangenetik, Schlangenzahl 14, 35392 Giessen, Germany. Tel.: +49 641 99 41600; Fax: +49 641 99 41609; E-mail: [email protected].
and the generation of peptides of 39–42 amino acids (amyloid- (A)1-39 - A1-42 ) with A1-40 being the most common. In addition to either presenilin 1 or presenilin2, ␥-secretase is composed of the integral membrane proteins nicastrin, APH-1 (anterior pharynx-defective 1), and PEN2 (presenilin enhancer 2) [1]. Mutations in PSEN1 or PSEN2 increase production of highly amyloidogenic A1-42 . APP codes for APP and mutations including point mutations, duplications, and deletions also increase generation of A1-42 . Mutations in PSEN1 are most common in familial EOAD (30%–70% of cases). APP and particularly PSEN2 mutations are much less frequent, amounting to 10%–15% and A transition at position 376 of the coding sequence (c.376G>A; cDNA.812G>A). This nucleotide change results in the substitution of the amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). The mutation is located in a region of exon 6 of PSEN2 that encodes part of the first hydrophilic loop (HL-I) of the protein. Numerous findings are consistent with pathogenicity of this mutation: 1) The c.376G>A mutation co-segregates with the disorder; 2) The exchange has not been found in controls and is not listed in common variant databases (1000 genomes, dbSNP, Exome Variant Server); 3) In silico analysis using the MutationTaster tool (http://www.mutationtaster.org; [3]) predicts the disease causing nature of the p.E126K change with a high security score. Furthermore a PolyPhen-2 analysis (http://genetics.bwh.harvard.edu/pph2/; [4]) classifies the exchange as “probably damaging” as well with the highest possible score of 1.0. Substitution of the positively charged glutamic acid by the negatively charged lysine makes an effect on structural and functional integrity of the protein likely; and 4) The mutation affects an evolutionarily highly conserved amino acid (Fig. 2) suggesting an important function of E126 within HL-I.
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Fig. 1. Pedigree of the family. The index patient is marked by arrow. Sequencing chromatograms are given of both strands (A, forward; B, reverse) of exon 6 of the index patient’s and her mother’s PSEN2 gene.
Fig. 2. Evolutionary conservation of E126 of PSEN2 orthologs. Protein identifier numbers are given on the right. The conserved amino acid glutamic acid residue at position 126 is highlighted in red. Nonconserved amino acids are depicted in green.
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Given that only one additional proven pathogenic substitution of an amino acid (threonine at position 122) in a hydrophilic loop of PSEN2 has been found in EOAD patients [21, 22], it is of special interest to compare their phenotypes with those of the present cases. Age of onset of the patients with the previously described mutations in HL-I (p.T122R and p.T122P) had a comparable age of onset as the two molecularly tested members of the present family. Two members of the family with the p.T122R mutation [22] had disease onset at 55 and 57 years of age. Disease onset in the two (unrelated) patients with the p.T122P mutation was 47 and 50 years [21]. The phenotype of members of the family carrying the p.T122R mutation [22] differed remarkably from the present cases (p.E126K) and those carrying the p.T122P mutation. Disease progressed fairly rapidly in one patient of the p.T122R mutation family and he was “unable to speak and bedridden” after a course of five years. His sister with disease onset at 57, however, mainly displayed inAPPropriate behavior and “impairment in non-verbal short- and long-term memory, language comprehension, and verbal fluency with only mild impairment of verbal long-term memory”. A monozygotic twin of this patient was normal except for a “mild deficit of verbal long-term memory” at age 60. In summary, the present report describes a previously unrecognized pathogenic PSEN2 mutation in EOAD. Comparison to other cases carrying mutations of amino acids in HL-1 underlines the great phenotypic variability in patients with PSEN2 mutations. The report also emphasizes that clear genotype-phenotype correlations cannot be established in patients with PSEN2 mutations.
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Presently only 13 definitely pathogenic PSEN2 mutations have been documented (http://www.molgen. ua.ac.be/ADMutations; [5]). Designation of mutations is based on the assumption that the start codon (ATG) is located in exon 3. (It has been recently shown that the start codon is actually located in exon 4 of transcript ENST00000366783). Most of these pathogenic mutations segregated with the disease and result in amino acid substitutions at 11 positions of the protein. Mutations affect 8 amino acids of transmembrane (TM) domains of presenilin 2, i.e., Asn141 [6–8] and Val148 [9] of TM-II; Met174 [10] and Ser175 [11] of TM-III; Gln228 [12], Tyr231 [13], and Met239 [14–17] of TM-V; and Thr430 [18] of TM-IX. Of two additional pathogenic amino acid substitutions, one affected the N-terminal (A85V) [19], the other the C-terminal domain (D439A) [20] of PSEN2. Finally, substitutions of amino acid threonine at position 122 in the HL-I domain were described, i.e., p.T122P [21] and p.T122R [22]. It needs to be emphasized that segregation could not be shown beyond doubt in all cases owing to the high variability in age of onset of patients with PSEN2 mutations. Of note, Jayadev et al. [7] suggested that only seven of the 13 “pathogenic” mutations listed in the database are sufficiently well documented to be considered pathogenic, i.e., mutations of Ala85 (A85V), of Thr122 (T122P, T122R), of Asn141 (N141I), of Met 239 (M239V, M239I), and of Thr430 (T430M). In addition, they identified a two base pair deletion (c.342-343 delGA) that results in premature termination (K115Efx10). The present report demonstrates functional importance of an additional amino acid in hydrophilic domain I of PSEN2, i.e., glutamic acid at position 126. Disease onset of carriers of this mutation was during the end of the fifth decade in the index case and about a decade later (end of sixth decade) in her mother. Although the index patient’s grandmother (I/2) was reported not to have been affected, minor memory loss might not have been noticed by the family. This person’s sister (I/3) was reported to have been demented from age 60 onwards. However, it remains unknown whether there was reduced penetrance in this family (I/1 not affected) or whether disease manifestation was only mild in this patient. In fact, disease onset during the 8th decade has been described in patients with PSEN2 mutations [2]. The wide range of onset in this family is comparable to other cases with PSEN2 mutations. Furthermore, early cognitive impairment and seizures as observed in III/1 are also characteristic findings in patients with PSEN2 mutations.
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ACKNOWLEDGMENTS This work was supported by the Justus-LiebigUniversity Giessen (Germany). Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2235). REFERENCES [1]
[2]
Strooper B de, Iwatsubo T, Wolfe MS (2012) Presenilins and ␥-secretase: Structure, function, and role in Alzheimer disease. Cold Spring Harb Perspect Med 2, a006304. Bird TD (1999) Early-onset familial Alzheimer disease. In: GeneReviews™ [Internet], Pagon RA, Adam MP, Bird TD, et al., ed. University of Washington, Seattle, WA, 19932014. http://www.ncbi.nlm.nih.gov/books/NBK1236/, Last updated Octobe 18, 2012.
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Marcon G, Di Fede G, Giaccone G, Rossi G, Giovagnoli AR, Maccagnano E, Tagliavini F (2009) A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype. J Alzheimers Dis 16, 509-511. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775-778. Marcon G, Giaccone G, Cupidi C, Balestrieri M, Beltrami CA, Finato N, Bergonzi P, Sorbi S, Bugiani O, Tagliavini F (2004) Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol 63, 199-209. Walker ES, Martinez M, Brunkan AL, Goate A (2005) Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem 92, 294-301. Finckh U, Alberici A, Antoniazzi M, Benussi L, Fedi V, Giannini C, Gal A, Nitsch RM, Binetti G (2000) Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurol 54, 2006-2008. Ezquerra M, Lle´o A, Castellv´ı M, Queralt R, Santacruz P, Pastor P, Molinuevo JL, Blesa R, Oliva R (2003) A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. Arch Neurol 60, 1149-1151. Piscopo P, Marcon G, Piras MR, Crestini A, Campeggi LM, Deiana E, Cherchi R, Tanda F, Deplano A, Vanacore N, Tagliavini F, Pocchiari M, Giaccone G, Confaloni A (2008) A novel PSEN2 mutation associated with a peculiar phenotype. Neurology 70, 1549-1554. Lle´o A, Blesa R, Gendre J, Castellv´ı M, Pastor P, Queralt R, Oliva R (2001) A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer’s disease. Neurology 57, 1926-1928. Finckh U, M¨uller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A (2000) High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 66, 110-117. Binetti G, Signorini S, Squitti R, Alberici A, Benussi L, Cassetta E, Frisoni GB, Barbiero L, Feudatari E, Nicosia F, Testa C, Zanetti O, Gennarelli M, Perani D, Anchisi D, Ghidoni R, Rossini PM (2003) Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol 54, 832-836.
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[20]
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Schwarz JM, R¨odelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7, 575-576. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7, 248-249. Cruts M, Theuns J, Van Broeckhoven C (2012) Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 33, 1340-1344. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973-977. Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu C, Bird TD (2010) Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133, 1143-1154. Yu C, Marchani E, Nikisch G, M¨uller U, Nolte D, Hertel A, Wijsman EM, Bird TD (2010) The N141I mutation in PSEN2: Implications for the quintessential case of Alzheimer disease. Arch Neurol 67, 631-633. Lao JI, Beyer K, Fern´andez-Novoa L, Cacabelos R (1998) A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer’s disease. Neurogenetics 1, 293-296. Guerreiro RJ Baquero M, Blesa R, Boada M, Br´as JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, G´omez-Isla T, Hern´andez I, Lle´o A, Machado A, Mart´ınez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, P´erez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, S´anchez-Valle R, Santana I, T´arraga L, Valdivieso F, Singleton A, Hardy J, Clarim´on J (2010) Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging 31, 725-731. Piscopo P, Talarico G, Crestini A, Gasparini M, MalvezziCampeggi L, Piacentini E, Lenzi GL, Bruno G, Confaloni A (2010) A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer’s disease. J Alzheimers Dis 20, 43-47. Zekanowski C, Styczynska M, Peplonska B, Gabryelewicz T, Religa D, Ilkowski J, Kijanowska-Haladyna B, Kotapka-Minc S, Mikkelsen S, Pfeffer A, Barczak A, Luczywek E, Wasiak B, Chodakowska-Zebrowska M, Gustaw K, Laczkowski J, Sobow T, Kuznicki J, Barcikowska M (2003) Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer’s disease in Poland. Exp Neurol 184, 991-996.
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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-140399 IOS Press
3
4
roo f
2
Short Communication
Previously Unrecognized Missense Mutation E126K of PSEN2 Segregates with Early Onset Alzheimer’s Disease in a Family
or P
1
5
Ulrich M¨ullera,∗ , Pia Wintera , Claus Bolenderb and Dagmar Noltea
6
a Institute
7
b Gemeinschaftspraxis,
8
Handling Associate Editor: Luisa Benussi
dA
uth
of Human Genetics, Justus Liebig University, Giessen, Germany Schl¨uchtern, Germany
Accepted 25 March 2014
14
Keywords: Alzheimer’s disease, early onset Alzheimer disease, E126K PSEN2 mutation, familial segregation, PSEN2
15
INTRODUCTION
16 17 18 19 20 21 22 23 24 25 26 27
rre co
12
Early onset Alzheimer’s disease (EOAD) with an age of onset A) in PSEN2 in an EOAD patient and her likewise affected mother. This change results in the exchange of amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). Pathogenicity of the mutation is shown by segregation with disease, evolutionary conservation of E126, and in silico analysis of the mutation.
9 10
∗ Correspondence
to: Prof. Dr. med. U. M¨uller, Institut f¨ur Humangenetik, Schlangenzahl 14, 35392 Giessen, Germany. Tel.: +49 641 99 41600; Fax: +49 641 99 41609; E-mail: [email protected].
and the generation of peptides of 39–42 amino acids (amyloid- (A)1-39 - A1-42 ) with A1-40 being the most common. In addition to either presenilin 1 or presenilin2, ␥-secretase is composed of the integral membrane proteins nicastrin, APH-1 (anterior pharynx-defective 1), and PEN2 (presenilin enhancer 2) [1]. Mutations in PSEN1 or PSEN2 increase production of highly amyloidogenic A1-42 . APP codes for APP and mutations including point mutations, duplications, and deletions also increase generation of A1-42 . Mutations in PSEN1 are most common in familial EOAD (30%–70% of cases). APP and particularly PSEN2 mutations are much less frequent, amounting to 10%–15% and A transition at position 376 of the coding sequence (c.376G>A; cDNA.812G>A). This nucleotide change results in the substitution of the amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). The mutation is located in a region of exon 6 of PSEN2 that encodes part of the first hydrophilic loop (HL-I) of the protein. Numerous findings are consistent with pathogenicity of this mutation: 1) The c.376G>A mutation co-segregates with the disorder; 2) The exchange has not been found in controls and is not listed in common variant databases (1000 genomes, dbSNP, Exome Variant Server); 3) In silico analysis using the MutationTaster tool (http://www.mutationtaster.org; [3]) predicts the disease causing nature of the p.E126K change with a high security score. Furthermore a PolyPhen-2 analysis (http://genetics.bwh.harvard.edu/pph2/; [4]) classifies the exchange as “probably damaging” as well with the highest possible score of 1.0. Substitution of the positively charged glutamic acid by the negatively charged lysine makes an effect on structural and functional integrity of the protein likely; and 4) The mutation affects an evolutionarily highly conserved amino acid (Fig. 2) suggesting an important function of E126 within HL-I.
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Fig. 1. Pedigree of the family. The index patient is marked by arrow. Sequencing chromatograms are given of both strands (A, forward; B, reverse) of exon 6 of the index patient’s and her mother’s PSEN2 gene.
Fig. 2. Evolutionary conservation of E126 of PSEN2 orthologs. Protein identifier numbers are given on the right. The conserved amino acid glutamic acid residue at position 126 is highlighted in red. Nonconserved amino acids are depicted in green.
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Given that only one additional proven pathogenic substitution of an amino acid (threonine at position 122) in a hydrophilic loop of PSEN2 has been found in EOAD patients [21, 22], it is of special interest to compare their phenotypes with those of the present cases. Age of onset of the patients with the previously described mutations in HL-I (p.T122R and p.T122P) had a comparable age of onset as the two molecularly tested members of the present family. Two members of the family with the p.T122R mutation [22] had disease onset at 55 and 57 years of age. Disease onset in the two (unrelated) patients with the p.T122P mutation was 47 and 50 years [21]. The phenotype of members of the family carrying the p.T122R mutation [22] differed remarkably from the present cases (p.E126K) and those carrying the p.T122P mutation. Disease progressed fairly rapidly in one patient of the p.T122R mutation family and he was “unable to speak and bedridden” after a course of five years. His sister with disease onset at 57, however, mainly displayed inAPPropriate behavior and “impairment in non-verbal short- and long-term memory, language comprehension, and verbal fluency with only mild impairment of verbal long-term memory”. A monozygotic twin of this patient was normal except for a “mild deficit of verbal long-term memory” at age 60. In summary, the present report describes a previously unrecognized pathogenic PSEN2 mutation in EOAD. Comparison to other cases carrying mutations of amino acids in HL-1 underlines the great phenotypic variability in patients with PSEN2 mutations. The report also emphasizes that clear genotype-phenotype correlations cannot be established in patients with PSEN2 mutations.
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Presently only 13 definitely pathogenic PSEN2 mutations have been documented (http://www.molgen. ua.ac.be/ADMutations; [5]). Designation of mutations is based on the assumption that the start codon (ATG) is located in exon 3. (It has been recently shown that the start codon is actually located in exon 4 of transcript ENST00000366783). Most of these pathogenic mutations segregated with the disease and result in amino acid substitutions at 11 positions of the protein. Mutations affect 8 amino acids of transmembrane (TM) domains of presenilin 2, i.e., Asn141 [6–8] and Val148 [9] of TM-II; Met174 [10] and Ser175 [11] of TM-III; Gln228 [12], Tyr231 [13], and Met239 [14–17] of TM-V; and Thr430 [18] of TM-IX. Of two additional pathogenic amino acid substitutions, one affected the N-terminal (A85V) [19], the other the C-terminal domain (D439A) [20] of PSEN2. Finally, substitutions of amino acid threonine at position 122 in the HL-I domain were described, i.e., p.T122P [21] and p.T122R [22]. It needs to be emphasized that segregation could not be shown beyond doubt in all cases owing to the high variability in age of onset of patients with PSEN2 mutations. Of note, Jayadev et al. [7] suggested that only seven of the 13 “pathogenic” mutations listed in the database are sufficiently well documented to be considered pathogenic, i.e., mutations of Ala85 (A85V), of Thr122 (T122P, T122R), of Asn141 (N141I), of Met 239 (M239V, M239I), and of Thr430 (T430M). In addition, they identified a two base pair deletion (c.342-343 delGA) that results in premature termination (K115Efx10). The present report demonstrates functional importance of an additional amino acid in hydrophilic domain I of PSEN2, i.e., glutamic acid at position 126. Disease onset of carriers of this mutation was during the end of the fifth decade in the index case and about a decade later (end of sixth decade) in her mother. Although the index patient’s grandmother (I/2) was reported not to have been affected, minor memory loss might not have been noticed by the family. This person’s sister (I/3) was reported to have been demented from age 60 onwards. However, it remains unknown whether there was reduced penetrance in this family (I/1 not affected) or whether disease manifestation was only mild in this patient. In fact, disease onset during the 8th decade has been described in patients with PSEN2 mutations [2]. The wide range of onset in this family is comparable to other cases with PSEN2 mutations. Furthermore, early cognitive impairment and seizures as observed in III/1 are also characteristic findings in patients with PSEN2 mutations.
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ACKNOWLEDGMENTS This work was supported by the Justus-LiebigUniversity Giessen (Germany). Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2235). REFERENCES [1]
[2]
Strooper B de, Iwatsubo T, Wolfe MS (2012) Presenilins and ␥-secretase: Structure, function, and role in Alzheimer disease. Cold Spring Harb Perspect Med 2, a006304. Bird TD (1999) Early-onset familial Alzheimer disease. In: GeneReviews™ [Internet], Pagon RA, Adam MP, Bird TD, et al., ed. University of Washington, Seattle, WA, 19932014. http://www.ncbi.nlm.nih.gov/books/NBK1236/, Last updated Octobe 18, 2012.
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Marcon G, Di Fede G, Giaccone G, Rossi G, Giovagnoli AR, Maccagnano E, Tagliavini F (2009) A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype. J Alzheimers Dis 16, 509-511. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775-778. Marcon G, Giaccone G, Cupidi C, Balestrieri M, Beltrami CA, Finato N, Bergonzi P, Sorbi S, Bugiani O, Tagliavini F (2004) Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol 63, 199-209. Walker ES, Martinez M, Brunkan AL, Goate A (2005) Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem 92, 294-301. Finckh U, Alberici A, Antoniazzi M, Benussi L, Fedi V, Giannini C, Gal A, Nitsch RM, Binetti G (2000) Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurol 54, 2006-2008. Ezquerra M, Lle´o A, Castellv´ı M, Queralt R, Santacruz P, Pastor P, Molinuevo JL, Blesa R, Oliva R (2003) A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. Arch Neurol 60, 1149-1151. Piscopo P, Marcon G, Piras MR, Crestini A, Campeggi LM, Deiana E, Cherchi R, Tanda F, Deplano A, Vanacore N, Tagliavini F, Pocchiari M, Giaccone G, Confaloni A (2008) A novel PSEN2 mutation associated with a peculiar phenotype. Neurology 70, 1549-1554. Lle´o A, Blesa R, Gendre J, Castellv´ı M, Pastor P, Queralt R, Oliva R (2001) A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer’s disease. Neurology 57, 1926-1928. Finckh U, M¨uller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A (2000) High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 66, 110-117. Binetti G, Signorini S, Squitti R, Alberici A, Benussi L, Cassetta E, Frisoni GB, Barbiero L, Feudatari E, Nicosia F, Testa C, Zanetti O, Gennarelli M, Perani D, Anchisi D, Ghidoni R, Rossini PM (2003) Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol 54, 832-836.
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