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A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid
Abstract
Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.
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“The accumulation of intraneuronal Aβ42 has been observed in the brains of AD patients and APP transgenic mice, and studies suggest that intraneuronal Aβ42 plays a role in neurodegenerative processes relevant to AD (reviewed in [7-9]).”
From Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation (2013) · cites this paper as [8]
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“…the - and -secretase cleavage sites either elevate the production of total A , as is the case with the K670N/ M671L substitution [Swedish mutation (Mullan et al., 1992a)], or increase the generation of A 42 specifically, as occurs with the I716V [Florida mutation (Eckman et al., 1997)] and V717I…”
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Self-citation
Metadata
- Authors
- Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad, B., & Lannfelt, L.
- Affiliations
- University of South Florida (US)
- Karolinska Institutet (SE)
- St Mary's Hospital (GB)
- Venue
- Nature Genetics
- Published
- 1992-08
- Volume
- 1
- Issue
- 5
- Pages
- 345-347
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2030641075
- Cited by
- 1,513
- References
- 22
- Citations by year
- 2026: 24 · 2025: 30 · 2024: 50 · 2023: 47 · 2022: 49 · 2021: 46 · 2020: 52 · 2019: 56 · 2018: 48 · 2017: 48 · 2016: 47 · 2015: 31 · 2014: 62 · 2013: 31 · 2012: 32
- FWCI
- 49.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, APP gene, amyloid-beta, early-onset familial Alzheimer's disease, Swedish families
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Base Sequence, Brain, Codon, Exons, Female, Humans, Genetic Linkage, Male, Middle Aged, Molecular Sequence Data, Oligodeoxyribonucleotides, Pedigree, Transcription, Genetic, Genetic Variation, Amyloid beta-Protein Precursor, Point Mutation
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