Pathogenicity: Alzheimer's Disease : Pathogenic, Progressive Nonfluent Aphasia : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Progressive Nonfluent Aphasia
Reference Assembly: GRCh37 (105)
Position: Chr14:73664802 G>T
dbSNP ID: rs63749891
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: AGA to ATA
Research Models: 1
This mutation was detected in two siblings from a pedigree with four affected members over three generations (Godbolt et al., 2004). The clinical presentation of disease in this family was atypical. Neither of the two individuals for which detailed clinical information was available met criteria for AD. In both cases, the disease was characterized by early language impairment with relative preservation of episodic memory. Specifically, one family member presented with word-finding difficulty and speech impairment at the age of 48. Over the next eight years her condition deteriorated and she developed mutism, rigidity, myoclonus of the upper limbs, and a shuffling gait. She was diagnosed with progressive nonfluent aphasia (PNFA). Her brother developed symptoms at age 51. He also had word-finding difficulties along with impairments in other executive functions. His disease, described as an atypical clinical syndrome, was suspected to be an atypical presentation of AD.
Unknown. MRI in both cases showed multiple white matter-foci with no or minimal atrophy.
In vitro this mutation impairs endoproteolysis of presenilin-1 and causes a selective increase in secreted Aβ43 (Nakaya et al., 2005).
A knock-in mouse model expressing human presenilin-1 with the R278I mutation has been generated. As a homozygote it is embryonic lethal due to impaired endoproteolysis of presenilin-1 and loss of γ-secretase functioning. Heterozygous mice are viable and overproduce Aβ43. When crossed to an APP transgenic model, APP23, double mutants developed high levels of Aβ43 and accelerated amyloid pathology (Saito et al., 2011).
Research Models Citations
- Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC. Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci. 2011 Aug;14(8):1023-32. PubMed.
- Godbolt AK, Beck JA, Collinge J, Garrard P, Warren JD, Fox NC, Rossor MN. A presenilin 1 R278I mutation presenting with language impairment. Neurology. 2004 Nov 9;63(9):1702-4. PubMed.
- Nakaya Y, Yamane T, Shiraishi H, Wang HQ, Matsubara E, Sato T, Dolios G, Wang R, De Strooper B, Shoji M, Komano H, Yanagisawa K, Ihara Y, Fraser P, St George-Hyslop P, Nishimura M. Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides. J Biol Chem. 2005 May 13;280(19):19070-7. PubMed.