Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1
Clinical Phenotype: Alzheimer's Disease, Myoclonic seizure, Myoclonus
Position: (GRCh38/hg38):Chr14:73171048 G>-
Position: (GRCh37/hg19):Chr14:73637756 G>-
dbSNP ID: rs63751475
Coding/Non-Coding: Both
DNA Change: Deletion
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Insertion
Codon Change: G to -
Genomic Region: Intron 4

Findings

This intronic mutation has been found in several British families and individual patients. 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).

Co-segregation with disease was established with the mutation being found in four affected family members, but not three members who remained asymptomatic and were older than the anticipated age at onset (Janssen et al., 2000). Linkage studies gave a LOD score of 3.72 and the mutation was considered to likely be fully penetrant.

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). Similar ages of onset were reported for another group of four patients from the United Kingdom whose disease progressed rapidly, with an approximate six year duration (Singleton et al., 2000). Symptoms included progressive cognitive decline, myoclonus, and seizures developing later in the disease. An additional case was reported in Rogaeva et al., 2001; no further details were published.

More recently, this mutation was identified in a retrospective analysis of genotypic and phenotypic data from individuals with autosomal-dominant familial AD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, U.K (Ryan et al., 2016). The study reported four British families, including a total of 17 affected individuals with a mean age at onset of 38 years. In nine patients with clinical records, myoclonus and seizures were observed in six and five individuals, respectively, and spastic paraparesis in one. Also, one patient presented with dyscalculia. Moreover, the mutation was also 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 (Sassi et al., 2014). 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.

Neuropathology

Postmortem examination revealed pathology consistent with AD. In one study, considerable neuronal loss in the hippocampus and entorhinal cortex and numerous neuritic plaques and neurofibrillary tangles in the hippocampus were reported. Pick bodies, cortical Lewy bodies, and cerebral amyloid angiopathy were absent (Tysoe et al., 1998). In another two cases, severe AD pathology was observed, including amyloid angiopathy, particularly evident in the cerebellum (Singleton et al., 2000).

Moreover, assessment of Aβ deposition in the cortical layers of four carriers showed individual variations but, in general, layer 3 had robust Aβ accumulation, while the deeper layers were less affected (Willumsen et al., 2021). Cerebral amyloid angiopathy was observed in the frontal cortices of three of these carriers. Also, two of the carriers had α-synuclein and TDP-43 pathology in the amygdala, and one had only TDP-43 pathology in the amygdala.

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, undetectable in brain homogenates and lymphoblast lysates of mutation carriers, 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). Also, detergent-resistant membranes isolated from prefrontal cortices of two patient brains produced about 2.5 more Aβ42 peptide when incubated with a labeled APP C99 substrate than controls, resulting in an elevated Aβ42/Aβ40 ratio (Szaruga et al., 2015). Production of both Aβ40 and Aβ38 was reduced, as was the Aβ38/Aβ42 ratio, suggesting impairment of carboxypeptidase-like activity.

The variant’s effects on another γ-secretase substrate, the developmental regulator Notch, may also have pathogenic consequences. Premature neurogenesis was observed during the differentiation of induced pluripotent stem cells harboring the mutation in a 2D model of cortical differentiation, as well as in the generation of a 3D cerebral organoid (Arber et al., 2021). Moreover, examination of adult hippocampal neurogenesis in human post-mortem tissue revealed a trend toward reduced abundance of newborn neurons, possibly indicating a premature aging phenotype. Experiments using an isogenic allelic series of this variant suggested this effect is unlikely due to a simple loss-of-function (Arber et al., 2019).

This mutation has also been reported to cause a harmful response to inflammation. When induced pluripotent stem cells carrying the variant were chronically exposed to tumor necrosis factor, a proinflammatory cytokine, they produced toxic Aβ and α-synuclein extracellular aggregates (Whiten et al., 2020).

In silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021, Sassi et al., 2014).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Tysoe C, Whittaker J, Xuereb J, Cairns NJ, Cruts M, Van Broeckhoven C, Wilcock G, Rubinsztein DC. 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. De Jonghe C, Cruts M, Rogaeva EA, Tysoe C, Singleton A, Vanderstichele H, Meschino W, Dermaut B, Vanderhoeven I, Backhovens H, Vanmechelen E, Morris CM, Hardy J, Rubinsztein DC, St George-Hyslop PH, Van Broeckhoven C. 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. Janssen JC, Hall M, Fox NC, Harvey RJ, Beck J, Dickinson A, Campbell T, Collinge J, Lantos PL, Cipolotti L, Stevens JM, Rossor MN. Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study. Brain. 2000 May;123 ( Pt 5):894-907. PubMed.
4. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
5. Singleton AB, Hall R, Ballard CG, Perry RH, Xuereb JH, Rubinsztein DC, Tysoe C, Matthews P, Cordell B, Kumar-Singh S, De Jonghe C, Cruts M, Van Broeckhoven C, Morris CM. Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation. Brain. 2000 Dec;123 Pt 12:2467-74. PubMed.
6. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
7. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
8. Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Mann D, Snowden J, Neary D, Harris J, Bras J, ARUK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. 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.
9. Willumsen N, Poole T, Nicholas JM, Fox NC, Ryan NS, Lashley T. Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease. Brain Pathol. 2022 May;32(3):e13009. Epub 2021 Jul 28 PubMed.
10. Szaruga M, Veugelen S, Benurwar M, Lismont S, Sepulveda-Falla D, Lleo A, Ryan NS, Lashley T, Fox NC, Murayama S, Gijsen H, De Strooper B, Chávez-Gutiérrez L. Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
11. Arber C, Lovejoy C, Harris L, Willumsen N, Alatza A, Casey JM, Lines G, Kerins C, Mueller AK, Zetterberg H, Hardy J, Ryan NS, Fox NC, Lashley T, Wray S. Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis. Cell Rep. 2021 Jan 12;34(2):108615. PubMed.
12. Arber C, Villegas-Llerena C, Toombs J, Pocock JM, Ryan NS, Fox NC, Zetterberg H, Hardy J, Wray S. Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout. Brain Commun. 2019;1(1):fcz024. Epub 2019 Oct 14 PubMed.
13. Whiten DR, Brownjohn PW, Moore S, De S, Strano A, Zuo Y, Haneklaus M, Klenerman D, Livesey FJ. Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer's disease neurons. Brain Commun. 2020;2(2):fcaa146. Epub 2020 Sep 15 PubMed.
14. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Further Reading