Mutations

PSEN1 L113_I114insT (Intron4)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637756 G>-
dbSNP ID: rs63751475
Coding/Non-Coding: Both
Genomic Region: Intron 4
Mutation Type: Insertion/Deletion
Codon Change: G to -

Findings

This intronic mutation has been found in at least nine families. The mutation, which involves deletion of a single nucleotide (G) from the intron 4 splice-donor consensus sequence (GT), has multiple downstream effects, and is associated with the production of three alternative transcripts, including two with shifted reading frames resulting in a premature termination codon.

This mutation was first identified in two patients from England who had early onset Alzheimer’s disease. One individual (case 177) had a positive family history of early onset AD (six affected individuals over three generations) and an inheritance pattern consistent with autosomal-dominant transmission. Family history details were not available for the second case, known as case 142. The age at onset was not documented for either patient; however, they both died in their 40s. Segregation with disease could not be formally demonstrated due to lack of DNA from relatives (Tysoe et al., 1998).

The mutation was subsequently found in four additional British cases with early onset AD. Patient 593 had autopsy-confirmed AD; no family history data were available. Patient 79/95 died at age 41 with autopsy-confirmed AD and a positive family history consistent with autosomal-dominant transmission. Patient TOR122/2 had early onset dementia and a positive family history consistent with autosomal-dominant AD, but no autopsy confirmation. Patient 160/4/1 belongs to a previously reported pedigree known as F105/160 which is characterized by autosomal-dominant AD with linkage to chromosome 14. AD diagnosis was confirmed in family members at ages 42 and 45 years. Mean age of onset in F105/160 is 37 ± 3 years (range: 36 to 40 years). Genetic markers flanking the PSEN1 gene suggested that the six British families carrying this mutation were related by a common ancestor (De Jonghe et al., 1999).

This mutation has been reported in several additional patients. Two cases from the United Kingdom, known as patient 342 and patient 344, experienced symptom onset in their 30s, specifically at 34 and 37 years, respectively. The latter case had a confirmed postmortem diagnosis of AD (Janssen et al., 2003). An additional case was reported in Rogaeva et al., 2001; no further details were published.

More recently, this mutation was one of several rare variants detected by exome sequencing in a British cohort composed of 47 unrelated early onset Alzheimer’s disease cases and 179 elderly controls free of AD pathology. The mutation was detected in two AD cases and was absent in all controls. The mean age at onset was 41, with death occurring 10 years later (Sassi et al., 2014).

Neuropathology

Postmortem examination revealed pathology consistent with AD, including considerable neuronal loss in the hippocampus and entorhinal cortex and numerous neuritic plaques and neurofibrillary tangles in the hippocampus. Pick bodies, cortical Lewy bodies, and cerebral amyloid angiopathy were absent (Tysoe et al., 1998).

Biological Effect

This is a deletion of a single nucleotide (G) from the intron 4 splice-donor consensus sequence (GT), which alters splicing and leads to the production of three different transcripts: two deletion transcripts and one insertion transcript. The deletion transcripts result in the formation of C-truncated presenilin-1 proteins, whereas the insertion transcript produces a full-length presenilin-1 with one extra amino acid (T) inserted between codons 113 and 114. In vitro, only the cDNA for the insertion construct altered Aβ42 secretion, increasing levels about 3.4-fold, and also increasing the Aβ42/Aβ40 ratio (De Jonghe et al., 1999).

This mutation has been predicted to be possibly damaging in silico (Sassi et al., 2014).

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References

Paper Citations

  1. . A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am J Hum Genet. 1998 Jan;62(1):70-6. PubMed.
  2. . Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. Hum Mol Genet. 1999 Aug;8(8):1529-40. PubMed.
  3. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  4. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  5. . Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am J Hum Genet. 1998 Jan;62(1):70-6. PubMed.
  2. . Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. Hum Mol Genet. 1999 Aug;8(8):1529-40. PubMed.

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