Mutations

PSEN1 M139V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Atypical Dementia
Genomic Mutation Name (MET1): g.25618A>G
Genomic Mutation Name (NT1): g.42172A>G
dbSNP ID: rs63751037
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to GTG

Findings

This mutation has been reported in at least nine families from the U.S., Germany, and the U.K., among other locations. Like many mutations, the clinical presentation varies between kindreds, with some individuals presenting with an atypical form of Alzheimer’s disease. Undefined genetic factors are thought to be largely responsible for the phenotypic variability.

This mutation was first identified in two unrelated families from the U.K., F148 and F206 (Clark et al., 1995; 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.

This mutation was reported in a family known as AD family 1421 (Boteva et al., 1996). Further clinical details were not provided, but disease in this family had previously been shown to be linked to chromosome 14.

At least four German families have been identified. In one, a single individual was described with familial early-onset Alzheimer’s disease has been described. 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 snile plaques and neurofibrillary tangles consistent with a diagnosis of AD. Segregation with disease was not formerly 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 Alzheimer’s disease. Cognitive decline started at age 32 and myoclonic and tonic-clonic jerks developing as the disease progressed. Three generations of her family were affected, although segregation could not be formerly assessed (Hanisch et al., 2004).

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.

This mutation was also observed in African American family with autosomal-dominant rapidly progressive dementia and psychosis occurring early in the fifth decade of life (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 fifties from a cerebral hemorrhage, his mother was cognitively intact in her eighties. 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 temporal, parietal, frontal and occipital cortices. The neuropathology in this case was notable for prominent basal ganglia and cerebellar plaques.

Neuropathology

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). 

Biological Effect

In vitro, this mutation increases the Aβ42/Aβtotal ratio when expressed in COS-1 cells cotransfected with APP695 (Murayama et al., 1999).

Other studies have reported specific increases in the Aβ42/Aβ40 ratio in a variety of cells types, including CHO and HEK cells cotransfected with APP695 (Shioi et al., 2007) and H4 glioma cells cotransfected with APP695 with the Swedish mutation (Houlden et al., 2000).

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References

Paper Citations

  1. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. . Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.
  3. . Chromosome 14 linked familial Alzheimer's disease. A clinico-pathological study of a single pedigree. Brain. 1995 Feb;118 ( Pt 1):185-205. PubMed.
  4. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
  5. . Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain. 1997 Mar;120 ( Pt 3):491-501. PubMed.
  6. . Mutation analysis of presenillin 1 gene in Alzheimer's disease. Lancet. 1996 Jan 13;347(8994):130-1. PubMed.
  7. . Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer's disease patients. Ann Neurol. 1996 Aug;40(2):265-6. PubMed.
  8. . Early-onset Alzheimer's disease due to mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up of a patient with a mutation at codon 139. Eur Arch Psychiatry Clin Neurosci. 1998;248(3):123-9. PubMed.
  9. . High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.
  10. . Genotype-phenotype analysis in early-onset Alzheimer's disease due to presenilin-1 mutations at codon 139. Eur J Med Res. 2004 Jul 30;9(7):361-4. PubMed.
  11. . 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.
  12. . Presenilin 1 mutation in an african american family presenting with atypical Alzheimer dementia. Arch Neurol. 2003 Jun;60(6):884-8. PubMed.
  13. . Early-onset Alzheimer's disease with presenilin-1 M139V mutation: clinical, neuropsychological and neuropathological study. Eur J Neurol. 2003 May;10(3):319-23. PubMed.
  14. . The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999 Sep;122 ( Pt 9):1709-19. PubMed.
  15. . 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.
  16. . FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 PubMed.
  17. . Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol. 2000 Nov;48(5):806-8. PubMed.

Further Reading

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Alzheimer Disease & Frontotemporal Dementia Mutation Database