Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Atypical Dementia
Reference Assembly: GRCh37/hg19
Position: Chr14:73640350 A>G
dbSNP ID: rs63751037
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
This mutation has been reported in multiple families and individuals suffering from Alzheimer’s disease (AD) with a variety of ancestries, including European, African, and Asian. The clinical presentation varies between kindreds, with some individuals presenting with an atypical form of AD. Undefined genetic and/or epigenetic factors are thought to be largely responsible for the phenotypic variability.
This mutation was first identified in two unrelated families from the United Kingdom, F148 and F206, for which linkage analyses were performed (Clark et al., 1995; Hutton et al., 1996; Palmer et al., 1999). The family, known as F148, had seven affected individuals over three generations, one with neuropathologically confirmed Alzheimer’s disease. The mean age of onset in this family was 41 years. The disease in this family had been previously linked to chromosome 14 and was characterized by early dyscalculia, an impairment of speech production, and relative absence of anomia, difficulty recalling words or names (Kennedy et al. 1995).
The second family, F206, also had seven affected members over three generations and a mean age of onset of 39 years (Clark et al., 1995; Hutton et al., 1996). The pedigrees for both of these families are charted in Fox et al., 1996, along with clinical details and neuropathology. In brief, the individuals in these two pedigrees display similarities in their patterns of clinical progression. Myoclonic jerks and generalized seizures were common and began at a relatively early stage.
Of note, a subsequent study reported four families from the United Kingdom with a total of 18 affected members and an average age at onset of 40 years (Ryan et al., 2016). Associated phenotypes included behavioral alterations, myoclonus, seizures, and spastic paraparesis.
M139V was also reported in a family in the United States known as AD family 1421 (Boteva et al., 1996). Further clinical details were not provided, but disease in this family previously had been shown to be linked to chromosome 14.
At least five affected German families have been identified. In one, a single individual was described with familial early onset Alzheimer’s disease. Dementia in this patient began at approximately 40 years of age and was associated with an early onset of myoclonus, involuntary muscle twitching (Sandbrink et al., 1996).
The proband in a second German family first developed interruptions during his speech and social withdrawal at age 38. Although he did not complain of myoclonus, it was observed upon clinical examination. The proband had a family history of dementia with an affected grandmother, an affected mother, and two affected brothers. The age of onset of dementia in this family was between 42 and 45 years. Segregation with disease could not be assessed due to lack of DNA from family members (Hüll et al., 1998).
A third German patient with the M139V mutation was described who suffered from prominent extrapyramidal signs and ataxia. Symptoms first became apparent at age 32 and later manifestations included generalized seizures, akinetic mutism, and frequent myoclonic jerks. The patient's father and paternal grandfather died with dementia at age 41 and 46, respectively, and autopsy of both showed senile plaques and neurofibrillary tangles consistent with a diagnosis of AD. Segregation with disease was not formally assessed in this family, although the inheritance pattern was consistent with autosomal-dominant transmission (Finckh et al., 2000).
In a fourth German family, the proband was a 46-year-old female with early onset AD. Cognitive decline started at age 32 and myoclonic and tonic-clonic jerks developed as the disease progressed. Three generations of her family were affected, although segregation could not be formally assessed (Hanisch et al., 2004).
A fifth German carrier with AD symptoms starting at age 42 and a family history of disease was also reported (Fuentes et al., 2021). The family included seven affected individuals, spanning four generations. Detailed evaluations of behavioral and cognitive deficits were presented for the affected members, but genetic information was available only for the proband, Of note, age of death appeared to decrease across generations, with disease progression occurring faster in more recent generations.
This mutation has also been observed in a pair of Polish siblings, a brother and sister with age of onset at 40 years (Zekanowski et al., 2003). Both patients met NINCDS-ADRDA criteria for probable AD, but had slightly different clinical presentations, although progression was very rapid in both. The sister had memory, language, and praxis deficits leading to severe dementia and aphasia two years after onset. Her brother had prominent memory, visuospatial, and behavioral disturbances, although his language ability was relatively preserved. After two years, he was also severely demented.
An African-American family with autosomal-dominant rapidly progressive dementia and psychosis occurring early in the fifth decade of life also carried the mutation (Rippon et al., 2003). The two affected brothers had early personality changes, psychosis, and memory impairment. Later symptoms included rigidity, dystonia, myoclonus, and mutism. A clinical diagnosis of frontotemporal dementia or atypical AD was made, but the pathology observed in a temporal lobe biopsy, and later at autopsy, revealed AD. Both brothers carried the M139V mutation; one also carried a polymorphism in exon 7 of MAPT, A178T, which was also found in unaffected relatives. The brothers had a family history of dementia; their father, also African-American, had early onset dementia with psychosis and died in his sixth decade of life.
Another affected individual who was found to carry this mutation developed memory difficulties at age 46 (Larner et al., 2003). Dementia was not apparent in the family history: The patient was an only child, his father died in his 50s from a cerebral hemorrhage, and his mother was cognitively intact in her 80s. His symptoms did not include myoclonus spastic paraparesis, cerebellar signs, or gait disturbance. He died from myocardial infarction at the age of 50, approximately four years after disease onset. An autopsy confirmed AD (CERAD: definite Alzheimer’s disease; Braak stage VI.) Aβ plaques were dense in the temporal, parietal, frontal and occipital cortices. The neuropathology in this case was notable for prominent basal ganglia and cerebellar plaques.
M139V was also identified in several Asian individuals with AD. Three carriers were described in a large family of the Chinese Familial Alzheimer’s Disease Network with 12 affected members spanning three generations and a mean age at onset of 45 years (Jia et al., 2020). In addition, a man diagnosed with AD from a large cohort study in South China had symptoms emerging at 53 years of age (Jiao et al., 2021). He had a family history of AD and symptoms included memory loss, language impairment, and mental and behavioral alterations. Also, a Japanese woman with AD onset at age 41and an APOE3/4 genotype was described (Islam et al., 2022).
The mutation was also found in a DNA sample of a 69-year-old Caucasian man diagnosed with sporadic amyotrophic lateral sclerosis (Couthouis et al., 2014).
This variant was absent from the gnomAD variant database (v2.1.1, Jan 2022).
The neuropathology associated with the M139V mutation is generally reported to be consistent with AD but otherwise unremarkable. For example, Fox et al., 1997, reported that the pathology in two patients (one from family F148 and one from family F206) was consistent with a diagnosis of AD.
In the context of a study comparing the pathology of familial and sporadic AD patients, the M139V mutation was reported to be one of five PSEN1 mutations associated with a faster rate of neurofibrillary tangle formation and accelerated neuronal loss. Interestingly, the age of onset in the two M139V patients examined differed by more than 30 years (35 versus 69). In the younger patient, the amount of amyloid and the rate of neurofibrillary formation and neuronal loss were approximately twice that of the older affected relative (Gómez-Isla et al., 1999).
An autopsy of an unrelated M139V mutation carrier confirmed the diagnosis of AD (i.e., CERAD definite Alzheimer’s disease and Braak stage VI) revealing typical plaque pathology with particularly dense plaques in the temporal, parietal, frontal, and occipital cortices. Of note in this case were prominent basal ganglia and cerebellar plaques (Larner et al., 2003).
In a female carrier, Aβ deposition showed cortical layer 3 as being particularly affected, while lower cortical layers had very little Aβ pathology (Willumsen et al., 2021). Also, in this case, α-synuclein pathology was detected in the amygdala.
In addition, levels of cerebrospinal fluid biomarkers, including Aβ42 and tau, were consistent with AD in one carrier, even at an early disease stage when there were no MRI-detectable abnormalities (Fuentes et al., 2021).
Early studies showed the M139V mutant increases the Aβ42/Aβ40 ratio in a variety of cells types, including COS-1 cells co-transfected with APP695 (Murayama et al., 1999), CHO and HEK cells co-transfected with APP695 (Shioi et al., 2007), and H4 glioma cells co-transfected with APP695 with the Swedish mutation (Houlden et al., 2000). Consistent with these observations, experiments with isolated proteins showed M139V decreases Aβ40 and Aβ38 levels, while increasing Aβ42 and Aβ43 levels (Chávez-Gutiérrez et al., 2012; Sun et al., 2017). Reductions in Aβ38/Aβ42 and Aβ40/Aβ43 ratios were confirmed in a cell model (Chávez-Gutiérrez et al., 2012).
In vitro assays revealed that mutant γ-secretase activity is more sensitive to increased temperatures than the wild-type protein, suggesting the mutation destabilizes the enzyme-substrate interaction required for sequential Aβ peptide proteolysis, resulting in the release of longer Aβ peptides (Szaruga et al., 2017). In addition, a study comparing physiological versus maximal γ-secretase activity in mutant and wild-type enzymes concluded that M139V reduces catalytic capacity (Svedružić et al., 2015). Although an in vitro study reported increased processing of N-cadherin and normal ɛ-cleavage of APP and Notch (Chávez-Gutiérrez et al., 2012), a study in transfected cells expressing M139V PSEN1 found reduced levels of the APP intracellular domain, suggesting APP ɛ-cleavage may be disrupted (Pinnix et al., 2013).
More recent experiments, analyzing the Aβ peptidome of neurons derived from two patient iPSC lines, indicated this mutant increases Aβ42/Aβ40, Aβ42/Aβ38, and Aβ43/Aβ40 ratios, while lowering Aβ38/Aβ40 (Arber et al., 2019; see April 2019 news). The elevated ratios suggest inefficient carboxypeptidase activity, predisposing neurons to accumulate longer Aβ fragments. Moreover, mass spectrometric analysis showed the ratio of N-terminally truncated Aβ2-40 to Aβ40 was increased, while the Aβ11-40:Aβ40 ratio was decreased compared with controls. Consistently, two subsequent studies revealed decreases in the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Both of these ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated the M139 residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).
On the other hand, consistent with M139V having little effect on Notch endoproteolytic activity, it had only a modest effect on neurogenesis (Arber et al., 2021). Other PSEN1 mutations that disrupt Notch activity appear to alter neural stem cell biology in aging and disease.
M139V may have other effects relevant to AD, however. In one carrier with an APOE3/4 genotype, blood ApoE levels were reduced compared with those of non-carriers (Islam et al., 2022). This may be due to the disruption of PSEN1’s proposed role in ApoE secretion. Moreover, Western blot analyses revelead a high degree of variablilty in mutant protein levels, consistent with altered protein stability (Arber et al., 2019).
Although predictions from some in silico algorithms yielded conflicting results (Couthouis et al., 2014; Xiao et al., 2021), the variant's PHRED-scaled CADD score, which integrates diverse information, was above 20, suggesting a damaging effect (CADD v.1.6, Sep 2021).
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.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. M139V: The variant was reported in 3 or more unrelated patients with AD, and absent from controls.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M139V: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.
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.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
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)|
Last Updated: 26 Apr 2022
- Familial Alzheimer’s Mutations: Different Mechanisms, Same End Result
- Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
- CryoEM γ-Secretase Structures Nail APP, Notch Binding
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Other mutations at this position
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