Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.25620G>A
Genomic Mutation Name (NT1): g.42174G>A
dbSNP ID: rs63750522
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to ATC
This mutation was first reported in a family known as “Duke AD family 1674”. This family had previously been shown to have early-onset Alzheimer’s disease linked to chromosome 14. The M139I mutation was detected in two affected family members and was absent in two unaffected family members (Boteva et al., 1996).
Brain tissue from two cases carrying the M139I mutation was examined by immunohistochemistry; however, it was not clear in this report whether the individuals carried the G>A or G>C version of this mutation (Mathews et al., 2000). In contrast to the eight other presenilin mutations examined, pyramidal neurons in M139I brains showed neurofibrillary tangles labeled with PSEN1 antibodies. The authors speculated that the presenilin protein might become mislocalized during neurodegeneration, as the expression level of the protein and its processing were comparable to control brains and those with sporadic AD.
In vitro, the M139I mutation increases the Aβ42/Aβtotal ratio in COS-1 cells cotransfected with APP695 (Murayama et al., 1999).
- Boteva K, Vitek M, Mitsuda H, de Silva H, Xu PT, Small G, Gilbert JR. Mutation analysis of presenillin 1 gene in Alzheimer's disease. Lancet. 1996 Jan 13;347(8994):130-1. PubMed.
- Mathews PM, Cataldo AM, Kao BH, Rudnicki AG, Qin X, Yang JL, Jiang Y, Picciano M, Hulette C, Lippa CF, Bird TD, Nochlin D, Walter J, Haass C, Lévesque L, Fraser PE, Andreadis A, Nixon RA. Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease. Mol Med. 2000 Oct;6(10):878-91. PubMed.
- Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.