A mutation in Alzheimerʼs disease destroying a splice acceptor site in the presenilin-1 gene

Pérez‐Tur, Jordi; Froelich, Susanne; Prihar, Guy; Crook, Richard; Baker, Matt; Duff, Karen; Wragg, Michelle; Busfield, Frances; Lendon, Corinne; Clark, Robert F.; Roques, P; Fuldner, Rebecca A.; Johnston, Janet; Cowburn, Richard F.; Forsell, Charlotte; Axelman, Karin; Lilius, Lena; Houlden, Henry; Karran, Eric; Roberts, Gareth W.; Rossor, Martin N.; Adams, Mark D.; Hardy, John; Goate, Alison; Lannfelt, Lars; Hutton, Michael

doi:10.1097/00001756-199512290-00071

Cited by 50 publications

(72 citation statements)

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“…300 amino acids, is generated by cleavage of PSI and that the proteolytic site is located at or near the beginning of the large hydrophilic loop. This region of the protein contains a hotspot for Alzheimer mutations [4] and it has been reported that deletion of exon 9 (bp 857-942) can cause early-onset Alzheimer disease [14]. These genetic findings point to the possible importance for this part of the protein in the pathological processes leading to Alzheimer disease and encouraged us to study the effect of more remote mutations on proteolysis at this location.…”

Section: Discussionmentioning

confidence: 98%

“…Sequence analysis predicts integral membrane proteins, that contain seven putative transmembrane domains, a short hydrophilic amino-and carboxyl-terminal tail, and a large hydrophilic loop between the sixth and seventh membrane-spanning domain. All of the reported mutations that result in early-onset Alzheimer's disease are missense mutations, 24 in PSI [5 11] and two in PS2 [12,13], or mutations that affect the splicing without affecting the coding of the protein [14] and this has led to the hypothesis that they may result in a gain of (mis)function. This view is also consistent with a recent report describing that an intron polymorphism in the PSI gene is related to approx.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

et al. 1996

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The majority of cases of early-onset familial Alzheimer disease are caused by mutations in the recently identified presenilin 1 (PS1) gene, located on chromosome 14. PS1, a 467 amino acid protein, is predicted to be an integral membrane protein containing seven putative transmembrane domains and a large hydrophilic loop between the sixth and seventh membranespanning domain. We produced 7 monoclonal antibodies that react with 3 non-overlapping epitopes on the N-terminal hydrophilic tail of PS1. The monoclonal antibodies can detect the full-size PS1 at Mr 47 000 and a more abundant Mr 28 000 product in membrane extracts from human brain and human cell lines. PC12 cells transiently transfected with PS1 constructs containing two different Alzheimer mutations fail to generate the 28 kDa degradation product in contrast to PC12 cells transfected with wild-type PS1. Our results indicate that missense mutations in this form of familial Alzheimer disease may act via a mechanism of impaired proteolytic processing of PS1.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

et al. 1996

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“…8 Previously, two mutant transcripts lacking exons 4 and 9 of the PS1 gene have been identified in familial AD. 9,10 We reported the preferential expression of a characteristic splicing variant of the PS2 gene that lacks exon 5 (isoform termed PS2V) in the sporadic AD brain, which is not caused by a mutation of the gene but possibly by a trans-acting factor. 11 We showed that PS2V protein impaired the signaling pathway of the unfolded protein response, in a manner similar to familial AD-linked PS1 mutant proteins, and caused significant increases in the production of Ab protein.…”

Section: Introductionmentioning

confidence: 99%

Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease

et al. 2003

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The aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, is a diagnostic feature of sporadic Alzheimer's disease (AD). We found PS2V is hypoxia-inducible in human neuroblastoma SK-N-SH cells. We purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the high mobility group A1a protein (HMGA1a; formerly HMG-I). HMGA1a bound to a specific sequence on exon 5, located upstream of the 5 0 splice site. HMGA1a expression was induced by hypoxia and the protein was accumulated in the nuclear speckles with the endogenous splicing factor SC35. Overexpression of HMGA1a generated PS2V, but PS2V was repressed by cotransfection with the U1 snRNP 70K protein that has a strong affinity to HMGA1a. HMGA1a could interfere with U1 snRNP binding to the 5 0 splice site and caused exon 5 skipping. HMGA1a levels were significantly increased in the brain tissue from sporadic AD patients. We propose a novel mechanism of sporadic AD that involves HMGA1a-induced aberrant splicing of PS2 premRNA in the absence of any mutations.

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“…The PS-1 gene consists of 10 coding (exons [3][4][5][6][7][8][9][10][11][12] and three non-coding exons (exons 1A, 1B and 2) which specify a 467-amino acid protein predicted to contain 6-9 1-4 transmembrane domains and to include a large hydrophilic loop region (amino acids 267-403). To date, more than 90 different mutations, 1,[5][6][7][8][9][10][11] mainly missense mutations, in the PS-1 gene have been identified in more than 90 families of various ethnic origins. 12 These mutations are highly penetrant, resulting in an early age of onset.…”

Section: Introductionmentioning

confidence: 99%

Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population

et al. 2002

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Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of earlyonset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-⑀4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P Ͻ 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.

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A mutation in Alzheimerʼs disease destroying a splice acceptor site in the presenilin-1 gene

Cited by 50 publications

References 0 publications

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease

Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population

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