Mutations

APP L705V

Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37 (105)
Position: Chr21:27264132 C>G
dbSNP ID: rs63750921
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to GTC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was first reported in a three-generation Italian family with autosomal-dominant, recurrent hemorrhagic stroke in the fifth to eighth decade of life (Obici et al., 2005).

A second instance of this mutation was reported in 2020 (Kozberg et al., 2020). At age 62, the carrier suffered multiple, large intracerebral hemorrhages over a four-month period, the last of which was fatal. Notably, except for brief periods immediately following each hemorrhage, her cognition remained intact. As in the original report of this mutation, there is a family history of hemorrhagic strokes in individuals in their 40s to 70s that is consistent with an autosomal dominant pattern of inheritance. Genetic information was not available from family members, precluding segregation analysis. This family is of English and Welsh ancestry and is not believed to be related to the Italian family described above.

Neuropathology

Pathological examination of the Italian carrier revealed severe cerebral amyloid angiopathy with evidence of hemorrhages originating from affected vessels and cracking of the vessel walls, creating a “vessel-within-vessel” appearance. The amyloid deposition appeared to selectively affect vessel walls. There was no evidence of Aβ parenchymal deposits (either diffuse or neuritic plaques), nor were neurofibrillary tangles or dystrophic neurites observed (Obici et al., 2005).

Similar to the Italian carrier, the carrier described in 2020 exhibited severe CAA—most prominent in leptomeningeal vessels—but no parenchymal amyloid plaques or neurofibrillary tangles (Kozberg et al., 2020).

Biological Effect

The biological effect of this mutation is unknown. Of note, the amino acid lies within a cholesterol-binding site as determined by NMR resonance spectroscopy and site-directed mutagenesis (Barrett et al., 2012).

Last Updated: 15 May 2020

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References

Paper Citations

  1. . A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol. 2005 Oct;58(4):639-44. PubMed.
  2. . Hereditary cerebral amyloid angiopathy, Piedmont-type mutation. Neurol Genet. 2020 Apr;6(2):e411. Epub 2020 Mar 13 PubMed.
  3. . The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science. 2012 Jun 1;336(6085):1168-71. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol. 2005 Oct;58(4):639-44. PubMed.

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