Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173631 A>G
Position: (GRCh37/hg19):Chr14:73640339 A>G
dbSNP ID: rs63751278
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to AGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was reported in a Greek family with a history of Alzheimer’s disease in which two cousins were found to carry the mutation. One of the mutation carriers, p.42, presented at age 33 with a mild deficit in short-term memory. Two years later, she had severe dementia, myoclonic jerks, and epilepsy. Her brother experienced symptom onset at age 36 and a biopsy of his frontal cortex three years later showed signs of advanced AD. Their 40-year-old cousin (p.41), also carried the N135S mutation and presented with mild memory deficits at age 35, gait disorder at age 36, and limb spasticity and ataxia at age 39. Three siblings in the previous generation and the common grandfather were also affected and died between the ages of 40 and 42  (Finckh et al., 2005).

Similar clinical features, including limb spasticity and seizures, were noted in members of a second family with the N135S mutation (Rudzinski et al., 2008). The family had three affected members, a mother and her two children, all of whom developed dementia beginning in their 30s. Both children had an unusual phenotype for AD, with prominent spastic dysarthria and limb spasticity, although these symptoms were not documented in their mother. The mother first developed signs of cognitive impairment in her early 30s, and later developed seizures. After eight years of illness, she died at age 40.

The daughter presented with memory problems at age 32. By age 37 she had problems producing speech, specifically dysarthria, gait unsteadiness, and agitation. Like her mother, she also developed seizures. She died around age 38. She carried the mutation.

The son presented with memory difficulties at age 33. At age 40 he reported increasing difficulty at work due to impairments in executive functions and short-term memory. He later developed dysarthria, balance difficulties, and gait unsteadiness. Like his sister, he was a mutation carrier.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Autopsy of the mother and daughter confirmed the diagnosis of AD, with widespread neurofibrillary tangles and neuritic plaques. Mild amyloid angiopathy was also noted. Some cotton-wool plaques were observed, but most of the plaques were neuritic and had dense amyloid cores. Corticospinal-tract pathology was detected in both cases, but was more pronounced in the mother, contrasting with her lack of documented motor symptoms (Rudzinski et al., 2008).

Biological Effect

A study that examined the full set of Aβ peptides generated by this variant in transfected cells revealed an increase in toxic Aβ43 and a decrease in Aβ37, an indicator of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Importantly, like known pathogenic mutations, this variant decreased the Aβ37/Aβ42 ratio, a measurement that outperformed the Aβ42/Aβ40 ratio as a biomarker for distinguishing between control and AD samples.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

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.

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References

Paper Citations

1. Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
2. Rudzinski LA, Fletcher RM, Dickson DW, Crook R, Hutton ML, Adamson J, Graff-Radford NR. Early onset familial Alzheimer Disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1. Alzheimer Dis Assoc Disord. 2008 Jul-Sep;22(3):299-307. PubMed.
3. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
4. 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.

External Citations

1. gnomAD v2.1.1
2. Apr 2022 news

Further Reading

No Available Further Reading