Mutations

PSEN1 H163R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73653568 A>G
dbSNP ID: rs63750590
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 1

Findings

H163R is a relatively frequent pathogenic mutation with numerous reports in different populations. At least 15 families have been identified worldwide, including in European countries, Japan, China, Canada, Turkey, Korea, and the United States.

The H163R mutation was first described in 1995 in conjunction with the cloning of the PSEN1 gene. It was detected in two families, one American (Pedigree 603) and one French-Canadian (Tor42). The mutation was shown to segregate with early onset familial Alzheimer’s disease in both families, the latter with onset around 45 years of age (Sherrington et al., 1995). This mutation was also detected in a French family, known as SAL001, with two affected family members (onset at 42 and 47 years) (Campion et al., 1995).

H163R was also detected in several Japanese families in the 1990s. In one large Japanese kindred, the mutation strongly segregated with disease: It was found in three affected individuals but was absent in three unaffected family members (Tanahashi et al., 1995). Two other Japanese families had familial AD with age at onset in the 40s (Kamino et al., 1996; Yagi et al., 2014). This mutation was also described in a young Japanese man with apparently sporadic AD. He experienced symptom onset at age 41 and met diagnostic criteria for AD (NINCDS-ADRDA). The mutation likely arose de novo, as his parents (82 and 76 years old) and two siblings (53 and 47 years old) were not affected by AD and were not mutation carriers. Genetic analysis confirmed paternity (Tanahashi et al., 1996). 

Multiple carriers of European ancestry were also described shortly after the variant's discovery. For example, the mutation was found in a Caucasian family of European descent living in Texas. This family had three siblings who met NINCDS-ADRDA criteria for AD. They developed symptoms in their 40s and were confirmed mutation carriers. They had a family history of dementia; their deceased father was also affected, but segregation with disease could not be assessed (Poduslo et al., 1996). Moreover, members of another family, referred to as 603, were diagnosed with early onset AD confirmed by postmortem examination of at least one individual (Boteva et al., 1996).

Additional carriers have been reported over the years. For example, the mutation was detected in two Polish sisters with fairly typical clinical presentations of early-onset AD. They developed symptoms at ages 50 and 51. The older sister developed severe dementia five years after the onset of the disease. The younger was mildly demented two years after the onset of symptoms. Their mother had died of dementia after developing symptoms at age 50. Segregation with disease could not be assessed (Zekanowski et al., 2003).

Of note, a large Spanish kindred carrying the H163R mutation with an estimated 35 affected individuals over five generations was also described. Detailed clinical details are available for five affected family members. The age of onset was noted to be rather homogenous in this family, in the mid-40s (mean 46, range: 42 to 50 years). Most of the cases developed typical AD, some with neuropsychiatric symptoms such as anxiety, apathy, depression, and/or irritability. Myoclonus and/or seizures were frequently observed in advanced stages (Gómez-Tortosa et al., 2010).

Moreover, a large dataset compiled from 28 French hospitals, reported six carriers from different families suffering from early onset AD (Lanoiselée et al., 2017). In one of the carriers, diagnosed with a frontal variant of AD with behavioral symptoms emerging at age 34 and myoclonic seizures, the mutation appeared to have arisen de novo (Lacour et al., 2019). 

A Turkish family known as AD-45 was also found to carry this mutation. The proband developed memory problems at the age of 41. Her dementia progressed rapidly and within two years she was unable to care for herself and had developed visual hallucinations. Her father had also suffered from dementia and died at the age of 51. Segregation with disease could not be assessed (Lohmann et al., 2012).

More recently, several studies of Asian families and individuals have identified multiple carriers afflicted by AD. Two carriers from Hong Kong, a woman and a man, developed symptoms at 42 and 41 years of age, respectively (Shea et al., 2015). The same year, a Chinese man with a family history of dementia was also reported as carrying the mutation (Shi et al., 2015). This individual developed memory loss at age 42 and was diagnosed with probable AD according to NINCDS-ADRDA criteria. His father had dementia by age 50 and died at age 60. Segregation with disease could not be assessed in this family. The mutation was subsequently reported to segregate with early onset AD in another Chinese family with at least five affected mutation carriers (Lin et al., 2016), and a report from the Chinese Familial Alzheimer’s Disease Network described a family with seven affected carriers (Jia et al., 2020). The mutation was also reported in a Korean woman with a strong family history of dementia (Park et al., 2020). She began having memory problems at age 46, and also developed parkinsonism, delusion, and compulsive behavior.

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

Neuropathology

Neuropathology consistent with AD has been reported (Boteva et al., 1996). Of note, an assessment of mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) observational study found that eight percent of individuals carrying this variant had more than five cerebral microhemorrhages per year, with the most severe case having more than 20 (Joseph-Mathurin et al., 2021). Also, one carrier was reported to have Lewy body pathology, as assessed by α-synuclein staining, in the amygdala, cingulate gyrus, neocortex, and substantia nigra (Leverenz et al., 2020).

At least two carriers had cerebrospinal fluid levels of Aβ42, tau, and phospho-tau consistent with AD (Lanoiselée et al., 2017). MRI showed diffuse brain atrophy in one case (Park et al., 2020), but revealed no cortical atrophy in a case diagnosed with a frontal variant of AD (Lacour et al., 2019). In the latter patient, PET/SPECT imaging revealed frontal and temporo-parietal hypometabolism, predominantly in the right hemisphere.

Biological Effect

Early studies showed that cultured cells expressing mutant PSEN1 had an increased Aβ42/Aβ total ratio (Murayama et al., 1999). Consistently, a subsequent cell-based study confirmed the elevated Aβ42/Aβ total ratio, and revealed increased levels of total Aβ, Aβ42, and Aβ43, and reduced levels of Aβ38, as well as Aβ40, when normalized for total Aβ production (Kakuda et al., 2021). However, in experiments with isolated proteins, the mutation was reported to reduce both Aβ40 and Aβ42 production to undetectable levels (Sun et al., 2017). 

This mutation has also been reported to affect cell functions beyond APP processing. For example, it appears to disrupt the γ-secretase-dependent processing of neurexin, a presynaptic cell adhesion protein (Saura et al., 2011). It has also been suggested to increase the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) which contain PSEN1 and are involved in phospholipid biosynthesis, cholesterol esterification, calcium transport, and homeostasis of mitochondria and the ER (Han et al., 2021).

Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Yagi et al., 2014Sala Frigerio et al., 2015; Park et al., 2020, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 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.

PS2-S

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. H163R: Functional observations are mixed, but most indicate damaging effects.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. H163R: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. H163R: Cosegregation demonstrated in >1 family.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Research Models

This mutation has been introduced into at least one mouse model of disease. See PSEN1-YAC (line G9).

Last Updated: 04 Mar 2022

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References

Research Models Citations

  1. PSEN1-YAC (line G9)

Paper Citations

  1. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  2. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  3. . Missense mutation of S182 gene in Japanese familial Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):440. PubMed.
  4. . Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.
  5. . Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 PubMed.
  6. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  7. . A presenilin 1 mutation in an early onset Alzheimer's family: no association with presenilin 2. Neuroreport. 1996 Aug 12;7(12):2018-20. PubMed.
  8. . Mutation analysis of presenillin 1 gene in Alzheimer's disease. Lancet. 1996 Jan 13;347(8994):130-1. PubMed.
  9. . Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
  10. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  11. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  12. . Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. PubMed.
  13. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  14. . A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences. J Formos Med Assoc. 2016 Feb;115(2):67-75. Epub 2015 Aug 31 PubMed.
  15. . Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord. 2015;39(1-2):32-40. Epub 2014 Oct 15 PubMed.
  16. . [Mutation analysis of presenilin 1 gene in a Chinese family affected with early-onset familial Alzheimer's disease]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016 Jun;33(3):324-7. PubMed.
  17. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  18. . Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e5-155.e8. Epub 2019 May 22 PubMed.
  19. . Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease. Neurology. 2021 Mar 23;96(12):e1632-e1645. Epub 2021 Jan 25 PubMed.
  20. . Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
  21. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  22. . Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  23. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  24. . Presenilin/γ-secretase regulates neurexin processing at synapses. PLoS One. 2011;6(4):e19430. PubMed.
  25. . Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function. Theranostics. 2021;11(18):8855-8873. Epub 2021 Aug 17 PubMed.
  26. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Other Citations

  1. Sala Frigerio et al., 2015

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

Papers

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.
  2. . Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
  3. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  4. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  5. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  6. . Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.
  7. . Somatic mutation analysis of the APP and Presenilin 1 and 2 genes in Alzheimer's disease brains. J Neurogenet. 1998 Jan;12(1):55-65. PubMed.
  8. . Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. Am J Hum Genet. 1996;59(Suppl):A252
  9. . Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants. Mol Neurobiol. 2016 Sep 19; PubMed.
  10. . On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.

Protein Diagram

Primary Papers

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  2. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  3. . Missense mutation of S182 gene in Japanese familial Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):440. PubMed.

Other mutations at this position

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