Mutations

APP D694N (Iowa)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Genome Build: 105
Position: Chr21:27264165 G>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 (Grabowski et al., 2001). 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.

The "Iowa mutation" was later found in a Spanish pedigree (Greenberg et al., 2003). 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

This mutation was also observed in two Irishwomen with early onset ICH who shared a common great-grandfather (Mok et al., 2014). In contrast to the Iowan and Spanish families, both of whom had fairly uniform familial presentations, the clinical course of the two Irishwomen varied. One patient, LM, had a history of chronic migraine headaches, but was cognitively normal at age 53 when she died of a brain hemorrhage. The second patient, DG, developed cognitive decline at age 51, and two years later experienced symptomatic ICH. A CT scan showed a right subcortical occipital lobe hemorrhage. Her father died in his 70s with dementia, 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.

Most recently, three members of a Polish family affected by hereditary ICH were found to carry the Iowa mutation (Iwanowski et al,. 2015). The pedigree shows seven affected individuals over three generations with an autosomal-dominant pattern of  inheritance. The proband presented at the age of 43 with neurological symptoms related to an ICH in the left occipital lobe. Her mother had her first stroke at age 40 and died at age 60 from ICH. Three of the proband’s brothers developed symptoms in middle age. Overall, symptom onset in this family ranged from 38 to 47 years of age.

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. . Iowa-type hereditary cerebral amyloid angiopathy in a Polish family. J Neurol Sci. 2015 Sep 15;356(1-2):202-4. Epub 2015 Jun 14 PubMed.
  5. . 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.
  6. . Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor. Ann N Y Acad Sci. 2002 Nov;977:258-65. PubMed.
  7. . 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

  1. 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.

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