Mutations

APP c.*331_*332del

Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Cerebral Amyloid Angiopathy
Coding/Non-Coding: Non-Coding
Mutation Type: Deletion
Genomic Region: 3' UTR

Findings

This deletion variant in the 3' untranslated region of APP was found in one out of 90 cases with cerebral amyloid angiopathy (CAA) (Nicolas et al., 2015). The patient was diagnosed with probable CAA on the basis of clinical findings and imaging. In brief, at the age of 39 he developed multiple spontaneous cortical hemorrhages. These were bilateral subarachnoid hemorrhages resulting in delirium. Several lobar hematomas followed in subsequent months, along with cortical microbleeds, diffuse superficial siderosis, and white-matter hyperintensities. No other sequence abnormalities were detected at the APP locus. The patient's APOE genotype was ε3/ε4. He had no family history of CAA. His unaffected mother did not carry the variant, suggesting possible segregation with disease. DNA from the patient’s father was unavailable, as he had died suddenly at the age of 70. The mutation carrier was of sub-Saharan African origin and the variant was absent in 175 controls originating from this region.

Note, this variant is named according to its position in the 3' UTR of APP. Nucleotides 331 and 332 in the UTR are deleted.

Neuropathology

Unknown. Imaging revealed multiple hemorrhages and hematomas in the temporal, frontal, and parietal regions of the cortex. These were lobar and subarachnoid hemorrhages. Diffuse superficial siderosis was observed, along with cortical microbleeds and white-matter hyperintensities.

Biological Effect

This variant in the 3' UTR of APP is a two base pair (TA) deletion. This deletion occurs in a highly conserved region of the UTR. When cloned into a luciferase reporter, the variant increased APP expression approximately 1.5-fold over wild-type levels. APP mRNA was similarly elevated in patient's blood. Follow-up experiments indicated that this upregulation was at least partially attributable to changes in miRNA binding.

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References

Paper Citations

  1. . Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy. Eur J Hum Genet. 2015 Apr 1; PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy. Eur J Hum Genet. 2015 Apr 1; PubMed.

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