Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3, PP4
Clinical Phenotype: Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type
Reference Assembly: GRCh37/hg19
Position: Chr21:27264168 G>C
dbSNP ID: rs63750579
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to CAA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 4

Findings

Carriers of this mutation develop a severe hereditary form of cerebral amyloid angiopathy (CAA), known as hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). This disease is associated with recurrent strokes during the fifth and sixth decades of life. In addition to severe hemorrhages, extensive amyloid develops in the vasculature. The mutation has been described in three Dutch families (Wattendorff et al., 1982; Luyendijk and Bots, 1986) and it is estimated that as many as 500 descendents of these families are at risk of the disease. An additional affected family of Dutch descent was described in Western Australia (Panegyres et al., 2005). The discovery of this mutation was an early demonstration that a variant in the APP gene could cause severe amyloid deposition (Levy et al., 1990; van Broeckhoven et al., 1990; Fernandez-Madrid et al., 1991).

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

Neuropathology

This mutation is associated with severe amyloid deposition in cerebral vessels, hemorrhages, and diffuse plaques in brain parenchyma (Timmers et al., 1990). Extensive Aβ accumulates in the cerebral vessels, especially the meningeal arteries and the cerebro-cortical arterioles. In people with HCHWA-D, the amount of CAA is correlated with dementia, whereas parenchymal plaque density and intraneuronal neurofibrillary tangles are not (Natté et al., 2001). In contrast to patients with AD, neurofibrillary tangles are not a prominent neuropathological feature of HCHWA-D.

Biological Effect

This mutation results in the accumulation of Aβ in cerebral vessel walls. This pathology leads to cell death and loss of vessel wall integrity, which in turn makes the vessels prone to obstruction and rupture, manifesting clinically as hemorrhages and infarcts. In vitro, this mutation accelerates Aβ aggregation, leading to increased fibril formation (Wisniewski et al., 1991). It also alters the processing of APP, increasing the relative quantities of Aβ beginning at Asp1, Val18, and Phe19 (Watson et al., 1999). This mutation is associated with high levels of β-sheet conformation and induction of apoptosis in cerebral endothelial cells compared with wild-type Aβ (Miravalle et al., 2000). Moreover, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, consistent with it having a deleterious effect (CADD v.1.6, Oct 2021).

Of note, E693 lies within a cholesterol-binding site as determined by NMR resonance spectroscopy and site-directed mutagenesis (Barrett et al., 2012).

Pathogenicity

Cerebral Amyloid Angiopathy : Pathogenic*

*Although not AD, the condition associated with this variant is inherited in an autosomal dominant manner, so its pathogenicity was classified using the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

Transgenic APP with the Dutch mutation has been introduced into several mouse lines that model CAA and vascular amyloid in AD. The models, such as the well-characterized Tg-SwDI and APPDutch mice, develop prominent vascular amyloid.

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References

Research Models Citations

1. Tg-SwDI (APP-Swedish,Dutch,Iowa)
2. APPDutch

Paper Citations

1. Wattendorff AR, Bots GT, Went LN, Endtz LJ. Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage. J Neurol Sci. 1982 Aug;55(2):121-35. PubMed.
2. Luyendijk W, Bots GT. Hereditary cerebral hemorrhage. Scand J Clin Lab Invest. 1986 Jun;46(4):391. PubMed.
3. Panegyres PK, Kwok JB, Schofield PR, Blumbergs PC. A Western Australian kindred with Dutch cerebral amyloid angiopathy. J Neurol Sci. 2005 Dec 15;239(1):75-80. Epub 2005 Oct 5 PubMed.
4. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990 Jun 1;248(4959):1124-6. PubMed.
5. Van Broeckhoven C, Haan J, Bakker E, Hardy JA, Van Hul W, Wehnert A, Vegter-Van der Vlis M, Roos RA. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science. 1990 Jun 1;248(4959):1120-2. PubMed.
6. Fernandez-Madrid I, Levy E, Marder K, Frangione B. Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage. Ann Neurol. 1991 Nov;30(5):730-3. PubMed.
7. Timmers WF, Tagliavini F, Haan J, Frangione B. Parenchymal preamyloid and amyloid deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis--Dutch type. Neurosci Lett. 1990 Oct 16;118(2):223-6. PubMed.
8. Natté R, Maat-Schieman ML, Haan J, Bornebroek M, Roos RA, van Duinen SG. Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol. 2001 Dec;50(6):765-72. PubMed.
9. Wisniewski T, Ghiso J, Frangione B. Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun. 1991 Nov 14;180(3):1528. PubMed.
10. Watson DJ, Selkoe DJ, Teplow DB. Effects of the amyloid precursor protein Glu693-->Gln 'Dutch' mutation on the production and stability of amyloid beta-protein. Biochem J. 1999 Jun 15;340 ( Pt 3):703-9. PubMed.
11. Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J. Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem. 2000 Sep 1;275(35):27110-6. PubMed.
12. Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science. 2012 Jun 1;336(6085):1168-71. PubMed.

Further Reading