Mutations

APP D694N (Iowa)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Genomic Mutation Name (MET1): g.275272G>A
Genomic Mutation Name (NT1): g.283968G>A
dbSNP ID: rs63749810
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GAT to AAT
Research Models: 2

Findings

This mutation was first documented in a large, three-generation kindred from Iowa. The family, who were of German descent, included 10 individuals affected by autosomal-dominant dementia beginning in the sixth or seventh decade of life. Progressive cognitive decline was the defining clinical feature. Postmortem examination was notable for microscopic hemorrhagic lesions (Grabowski et al., 2001).

This mutation was also found in a Spanish pedigree. Affected individuals presented with a hereditary syndrome involving hemorrhagic stroke, dementia, leukoencephalopathy, and occipital calcifications. Age of onset in this family was 58 to 66 years. A notable difference from the Iowa carriers was the presence of symptomatic intracerebral hemorrhage (ICH), which occurred in three of the four reported Spanish patients (Greenberg et al., 2003).

More recently, the D694 mutation was observed in two Irish women with early onset ICH who shared a common great-grandfather. In contrast to the Iowan and Spanish families, both of whom had fairly uniform familial presentations, the clinical course of the two Irish women varied. One patient, LM, had a history of chronic migraine headaches, but was cognitively normal at age 53 when she presented with sudden onset of severe headache and dysphasia. Within hours her neurological condition deteriorated and a large frontal lobe hematoma was seen by CT. Additional hemorrhages followed, leading to her death 34 days later. The second patient, DG, experienced symptoms of cognitive decline starting at age 51, and presented with the sudden onset of pounding headache and vomiting at age 53. A CT scan showed a right subcortical occipital lobe hemorrhage extending anteriorly into the right temporal lobe. The acute crisis resolved, and she was able to return home with support. Her father died in his 70s from a dementing illness, and a paternal aunt and grandmother suffered brain hemorrhages in their sixth and seventh decades. Additional relatives suffered from various neurologic conditions, including stroke, seizures, and a brain tumor, with three infants affected by fatal anencephaly (Mok et al., 2014).

Neuropathology

Neuropathological examination of the original Iowa proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and abundant Aβ40 in plaques. The proband and an affected brother also had microscopic hemorrhagic lesions and cortical calcifications in the occipital lobe (Grabowski et al., 2001). Neuropathological examination in the Irish patient, LM, confirmed a large occipital hemorrhage with severe amyloid angiopathy of meningeal, cerebro-cortical and cerebellar parenchymal arteries and veins. Calcification was observed in brain vessels, including those with and without amyloid. Some neuritic plaques and neurofibrillary tangles were seen along with tau-positive neuropil threads in the hippocampus and frontal and temporal neocortices. Her relative, DG, had a right subcortical occipital lobe hemorrhage visible by CT, which extended anteriorly into the right temporal lobe along with prominent calcifications (Mok et al., 2014). Neuropathologic data were not available from members of the Spanish pedigree (Greenberg et al., 2003).

Biological Effect

D694N corresponds to position 23 in Aβ (D23N) and has been shown to affect peptide structure in vitro resulting in the formation of a turn rather than a bend motif (Krone et al., 2008). Additional in vitro experiments have shown that the Iowa mutation promotes fibrillogenesis of Aβ and results in greater Aβ-induced toxicity (Van Nostrand et al., 2002; Van Nostrand et al., 2001).

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References

Paper Citations

  1. . Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001 Jun;49(6):697-705. PubMed.
  2. . Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. Neurology. 2003 Mar 25;60(6):1020-2. PubMed.
  3. . Familial cerebral amyloid angiopathy due to the iowa mutation in an irish family. Can J Neurol Sci. 2014 Jul;41(4):512-7. PubMed.
  4. . Effects of familial Alzheimer's disease mutations on the folding nucleation of the amyloid beta-protein. J Mol Biol. 2008 Aug 1;381(1):221-8. PubMed.
  5. . Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor. Ann N Y Acad Sci. 2002 Nov;977:258-65. PubMed.
  6. . Pathogenic effects of D23N Iowa mutant amyloid beta -protein. J Biol Chem. 2001 Aug 31;276(35):32860-6. Epub 2001 Jul 5 PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001 Jun;49(6):697-705. PubMed.