Mutations
PSEN1 M139K
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Overview
Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640351 T>A
dbSNP ID: rs63751106
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to AAG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5
Findings
This mutation was reported in a French woman (ALZ 034) with onset of symptoms at age 37. She met NINCDS-ADRDA criteria for probable AD and died at age 47. This may have been a case of a de novo mutation, as the woman had no family history of dementia. Her parents were unaffected at the age of 74 and neither had a family history of dementia. The mutation was absent in the woman’s mother (age 74) and brother (age 50) (Dumanchin et al., 1998). In a subsequent study, a French individual carrying this mutation with symptom onset at age 37 was reported as developing seizures at age 42 (Zarea et al. 2016).
Neuropathology
Unknown.
Biological Effect
Unknown. Multiple mutations at this position have been reported. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates M139 is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).
Last Updated: 25 Nov 2019
References
News Citations
Paper Citations
- Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, Agid Y, Martinez M, Clerget-Darpoux F, Frebourg T. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. J Med Genet. 1998 Aug;35(8):672-3. PubMed.
- Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
- Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, Agid Y, Martinez M, Clerget-Darpoux F, Frebourg T. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. J Med Genet. 1998 Aug;35(8):672-3. PubMed.
Other mutations at this position
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