Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891765 T>C
Position: (GRCh37/hg19):Chr21:27264077 T>C
dbSNP ID: rs63751122
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

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. The mutation was identified in the proband, but not in multiple unaffected family members indicating cosegregation with disease (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 some investigators have categorized as possibly pathogenic.

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

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). A subsequent study using purified His-tagged APP-C99 substrates, however, found that both Aβ42/Aβ40 and Aβ38/Aβ40 ratios generated from a mutant substrate were similar to those generated from a wild-type substrate, but ε-cleavage favored the generation of Aβ49 over Aβ48 peptides (Dimitrov et al., 2013). Consistent with these findings, NMR analyses and molecular dynamics simulations suggested L723P may cause local unfolding resulting in increased accessibility to water and cleavage at the Aβ49 site relative to the Aβ48 site (Bocharov et al., 2019).

A comprehensive survey of Aβ peptides produced from T719P, referred to as L52P, found reduced ε-cleavage and, consistent with previous studies, almost exclusive generation of Aβ48 (Devkota et al., 2021, Feb 2021 news). Also, interestingly, although Aβ48 does not include the L52P substitution, its trimming was nearly abrogated. Of note, Aβ48 is membrane-bound and may be pathogenic.

T719P’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 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

News Citations

1. Are the Long Aβ Peptides the Real Bad Guys? 5 Feb 2021

Paper Citations

1. Kwok JB, Li QX, Hallupp M, Whyte S, Ames D, Beyreuther K, Masters CL, Schofield PR. 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. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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. Dobricic V, Stefanova E, Jankovic M, Gurunlian N, Novakovic I, Hardy J, Kostic V, Guerreiro R. 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.
4. Dimitrov M, Alattia JR, Lemmin T, Lehal R, Fligier A, Houacine J, Hussain I, Radtke F, Dal Peraro M, Beher D, Fraering PC. Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat Commun. 2013;4:2246. PubMed.
5. Bocharov EV, Nadezhdin KD, Urban AS, Volynsky PE, Pavlov KV, Efremov RG, Arseniev AS, Bocharova OV. Familial L723P Mutation Can Shift the Distribution between the Alternative APP Transmembrane Domain Cleavage Cascades by Local Unfolding of the Ε-Cleavage Site Suggesting a Straightforward Mechanism of Alzheimer's Disease Pathogenesis. ACS Chem Biol. 2019 Jul 19;14(7):1573-1582. Epub 2019 Jun 19 PubMed.
6. Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.

Other Citations

1. R108Q

Further Reading

No Available Further Reading