Mutations

APP L723P (Australian)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.275360T>C
Genomic Mutation Name (NT1): g.284056T>C
dbSNP ID: rs63751122
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: CTG to CCG

Findings

This mutation was first identified in a three-generation Australian pedigree with clinical features consistent with early onset Alzheimer's disease. The mean age of onset in this family was 56 years (Kwok et al., 2000).

The L723P mutation was later identified in a large French study reporting 56 new families with autosomal-dominant, early onset Alzheimer’s disease. All probands met NINCDS-ADRDA criteria for probable AD and had a family history of disease (Wallon et al., 2012). The mutation was detected in one individual in a family known as ALZ 523, which had seven known affected family members. Only the genotype of the proband is known, therefore segregation with disease could not be determined. Age of onset in this family ranged from 54 to 57 years old, with an aggressive three- to four-year disease course. The mutation was classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

A Serbian AD patient has also been reported to carry the L723P mutation (Dobricic et al., 2012). He experienced symptom onset at age 45, including progressive cognitive deterioration and myoclonic jerks. His mother had died at age 60 with a diagnosis of probable AD, although segregation with disease could not be determined due to lack of DNA from family members. In addition to carrying a pathogenic APP mutation, this individual also carried a mutation in PSEN1 (R108Q), which is currently categorized as possibly pathogenic.

Neuropathology

Unknown.

Biological Effect

In CHO cells, this mutation was associated with elevated secreted Aβ42 (1.4- to 1.9-fold) compared with cells expressing wild-type APP (Kwok et al., 2000).

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References

Mutations Citations

  1. PSEN1 R108Q

Paper Citations

  1. . Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol. 2000 Feb;47(2):249-53. 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.
  3. . Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort. Neurobiol Aging. 2012 Jul;33(7):1481.e7-12. Epub 2012 Jan 4 PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol. 2000 Feb;47(2):249-53. PubMed.