Mutations

APP H677R (English)

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.269518A>G
Genomic Mutation Name (NT1): g.278214A>G
dbSNP ID: 63749953
Coding/Non-Coding: Coding
Genomic Region: Exon 16
Mutation Type: Point, Missense
Codon Change: CAT to CGT

Findings

This mutation was detected in one of two siblings in an English family known as "Family 209." The pathogenicity of the H677R variant is unclear because only one sibling carried the mutation, but both had neuropathologically confirmed Alzheimer's disease. Neither sibling had any known mutations in PSEN1 or PSEN2, and neither carried the APOE ε4 allele. Information is limited about the previous generation of this family. It is possible that the H677R variant is an autosomal-dominant pathogenic mutation, with disease in the noncarrier sibling due to a sporadic form. Alternatively, H677R may be a benign polymorphism not associated with disease, and both siblings were affected by sporadic AD. H677R was absent in 100 healthy, unrelated controls (Janssen et al., 2003).

Neuropathology

One mutation carrier had neuropathologically confirmed AD. A noncarrier sibling also had neuropathologically confirmed AD (Janssen et al., 2003).

Biological Effect

The H677R mutation causes an amino acid change within the Aβ region of APP, specifically altering the amino acid at position 6 of Aβ (H6R). The mutation does not affect Aβ production (Hori et al., 2007), but does alter the assembly kinetics of Aβ. Mutant Aβ peptides display accelerated secondary structure transitions and an increased propensity to form relatively large oligomers. The oligomers are also more efficient nucleators of fibril formation, and are significantly more cytotoxic than wild-type peptides (Ono et al., 2010).

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References

Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  2. . The Tottori (D7N) and English (H6R) familial Alzheimer disease mutations accelerate Abeta fibril formation without increasing protofibril formation. J Biol Chem. 2007 Feb 16;282(7):4916-23. PubMed.
  3. . Effects of the English (H6R) and Tottori (D7N) familial Alzheimer disease mutations on amyloid beta-protein assembly and toxicity. J Biol Chem. 2010 Jul 23;285(30):23186-97. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.