Mutations

PSEN1 S230N

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659492 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGT to AAT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

The PSEN1 S230N mutation was identified in a family of Northern European descent, enrolled in DIAN (Ringman et al., 2017). In the proband, symptoms began at age 57 with memory loss, bradykinesia, and prosopagnosia. Cognition progressively declined and atypical symptoms developed, including parkinsonism and hoarding behavior. MRI at age 65 showed diffuse atrophy, which was most pronounced in lateral temporal lobes and insulae; FDG-PET showed hypometabolism in parieto-temporal areas; CSF biomarkers (low Aβ42 and elevated total- and phospho-tau) were consistent with a diagnosis of AD.

The proband’s mother was reported to have had similar symptoms, beginning at age 59. A brother met the criteria for MCI at age 55 and for dementia at age 57. Two older sisters, ages 59 and 61, were unaffected, and had negative amyloid-PET scans and normal CSF biomarkers. The father of the affected siblings died at age 85 without dementia. Their maternal grandfather died of a myocardial infarction at age 47, and their maternal grandmother was cognitively normal at age 88.  This family history is consistent with an autosomal-dominant pattern of inheritance.

The proband and her affected brother were found to carry the S230N mutation, while the mutation was absent in the two unaffected sisters. This mutation is not found in the clinical provider’s own series of 13,006 chromosomes or in the Exome Variant Server or ExAC databases.

Two other pathogenic mutations have been identified at this residue, S230I and S230R.

Neuropathology

Unknown, but MRI showed diffuse atrophy, which was most severe in lateral temporal lobes and insulae.

Biological effect

Unknown, but predicted to be “not tolerated” by SIFT and “Probably Damaging” by PolyPhen-2. This mutation is classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

 

 

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References

Mutations Citations

  1. PSEN1 S230I
  2. PSEN1 S230R

Paper Citations

  1. . A novel PSEN1 (S230N) mutation causing early-onset Alzheimer's Disease associated with prosopagnosia, hoarding, and Parkinsonism. Neurosci Lett. 2017 Sep 14;657:11-15. Epub 2017 Jul 29 PubMed.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN1 (S230N) mutation causing early-onset Alzheimer's Disease associated with prosopagnosia, hoarding, and Parkinsonism. Neurosci Lett. 2017 Sep 14;657:11-15. Epub 2017 Jul 29 PubMed.

Other mutations at this position

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