Mutations

PSEN1 S290C;T291_S319del (ΔE9Finn)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Genomic Mutation Name (MET1): g.56681_61235del
Genomic Mutation Name (NT1): g.73292_77846del
dbSNP ID:
Coding/Non-Coding: Both
Genomic Region: Intron 8, Exon 9
Mutation Type: Complex
Codon Change:

Findings

This mutation involves the deletion of 4,555 nucleotides spanning exons 8, 9, and 10 of PSEN1 and results in the skipping of the entire exon 9. With the exception of the amino acids encoded by exon 9, an otherwise full-length protein is expressed. This was the first deletion mutation in PSEN1 reported to be pathogenic for AD (Crook et al., 1998; Prihar et al., 1999). There are now several known mutations that result in the exclusion of exon 9 due to deletion events as well as splice site mutations. These mutations are variously referred to as ΔE9, Δ9, delE9, or deltaE9.

This mutation has been observed in two Finnish families. It was first described in a pedigree known as Finn2, which had previously been shown to be affected by early-onset Alzheimer's disease due to a unidentified genomic change which resulted in the exclusion of exon 9 from PSEN1 transcripts (Crook et al., 1998). The reported pedigree contains 17 affected individuals over three generations. Disease in this family was characterized by progressive dementia frequently preceded by spastic paraparesis (SP). In this family onset of SP ranged from age 45 to 55 years and cognitive decline at 45 to 57 years. Death typically ocurred five to 12 years after onset. Additional clinical and neuroimaging data for this family, as well as an extended pedigree, are reported in Verkkoniemi et al., 2000.

In the second Finnish family, the same 4.6 kb deletion was found to be associated with disease over two generations (Hiltunen et al., 2000). In contrast to the Finn2 family, the clinical presentation of the four affected patients was typical for AD without indications of spastic paraparesis or any other major motor disturbance. The mean age at onset was 43.5 years. The E318G polymorphism in exon 9 of PSEN1 was also detected in two affected and eight healthy family members. The deletion mutation segregated with disease in this family and was absent in 102 unrelated AD patients and 51 control subjects from Finland.

Neuropathology

Neuropathological examination of two patients from the Finn2 pedigree revealed “unusual plaques” in addition to the typical amyloid plaques and neurofibrillary tangles of AD. The plaques were described as “reminiscent of loosely packed cotton wool balls” which were large (100-150 μM in diameter) and not congophilic, suggesting a lack of amyloid at the core (Crook et al., 1998). Cotton wool plaques have since been associated with multiple other PSEN1 mutations such as, I83_M84del, G217D, G217R, V261F, P264L, E280G, P284L, A431E, and DelT440.

Neuropathological findings were reported in one individual from the other Finnish family. In accordance with the clinical features, the pathology was typical of AD with numerous congophilic amyloid plaques, neurofibrillary tangles, neuritic plaques, and reactive astrocytes and microglia near plaques. Cerebral amyloid angiopathy was observed both in the parenchyma and in the leptomeninges. Cotton wool plaques were not observed. Overall, the neuropathology supported the diagnosis of definite AD according to CERAD criteria (Hiltunen et al., 2000).

Biological Effect

This is a deletion of 4.6 kb including the entire exon 9 and extending into the flanking intronic sequences. It results in an in-frame skipping of exon 9 and an amino acid change (S290C) at the splice junction of exons 8 and 10. Presenilin-1 protein lacking the region encoded by exon 9 is not subject to endoproteolytic processing in brains of transgenic mice (Lee et al., 1997), consistent with results in cultured mammalian cells (Thinakaran et al., 1996).

Research Models

Multiple mouse models which express PSEN1 lacking exon 9 have been developed. One line, referred to as S-9 (Lee et al., 1997), was subsequently bred to an APP transgenic mouse to generate a double transgenic (APPSwe/PSEN1dE9), which has a more severe phenotype than either of the parental lines. Another double transgenic model was made by coinjecting vectors expressing PSEN1ΔE9 and APP with the Swedish mutation (APPswe/PSEN1dE9). Although cotton wool plaques are sometimes prominent in the brains of AD patients with ΔE9 mutations, this pathology has not been observed in ΔE9 mouse models.

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References

Research Models Citations

  1. APPSwe/PSEN1dE9

Mutation Position Table Citations

  1. PSEN1 S290 Mutations

Mutations Citations

  1. PSEN1 E318G
  2. PSEN1 I83_M84del (DelIM)
  3. PSEN1 G217D
  4. PSEN1 G217R
  5. PSEN1 V261F
  6. PSEN1 P264L
  7. PSEN1 E280G
  8. PSEN1 P284L
  9. PSEN1 A431E
  10. PSEN1 T440del

Paper Citations

  1. . Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med. 1997 Jul;3(7):756-60. PubMed.
  2. . A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998 Apr;4(4):452-5. PubMed.
  3. . Alzheimer disease PS-1 exon 9 deletion defined. Nat Med. 1999 Oct;5(10):1090. PubMed.
  4. . Variant Alzheimer's disease with spastic paraparesis: clinical characterization. Neurology. 2000 Mar 14;54(5):1103-9. PubMed.
  5. . Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination?. Eur J Hum Genet. 2000 Apr;8(4):259-66. PubMed.
  6. . Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996 Jul;17(1):181-90. PubMed.

Other Citations

  1. APPswe/PSEN1dE9

Further Reading

Papers

  1. . Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol. 2000 Nov;48(5):806-8. PubMed.
  2. . Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease. Brain. 2014 Jul;137(Pt 7):1958-70. Epub 2014 May 24 PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998 Apr;4(4):452-5. PubMed.
  2. . Alzheimer disease PS-1 exon 9 deletion defined. Nat Med. 1999 Oct;5(10):1090. PubMed.

Other mutations at this position

View Table