Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease

Collin Y. Liu, Yu Ohki, Taisuke Tomita, Satoko Osawa, Bruce R Reed, William Jagust, Victoria Van Berlo, Lee-Way Jin, Helena C. Chui, Giovanni Coppola, John M. Ringman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. Objective: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. Methods: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. Results: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aβ42 and decreased APP and Notch intracellular domain production in vitro. Conclusion: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aβ.

Original languageEnglish (US)
Pages (from-to)1035-1041
Number of pages7
JournalJournal of Alzheimer's Disease
Volume58
Issue number4
DOIs
StatePublished - 2017

Fingerprint

Alzheimer Disease
Mutation
Amyloid Precursor Protein Secretases
Presenilin-1
Inheritance Patterns
Pyramidal Tracts
Myoclonus
Proteins
Memory Disorders
Parkinsonian Disorders
Short-Term Memory
Amyloid
Codon
Autopsy
Seizures
Amino Acids
Genes

Keywords

  • Autosomal dominant
  • familial Alzheimer's disease
  • gamma-secretase
  • P88L
  • presenilin-1 (PSEN1)
  • transmembrane domain
  • V89L

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. / Liu, Collin Y.; Ohki, Yu; Tomita, Taisuke; Osawa, Satoko; Reed, Bruce R; Jagust, William; Van Berlo, Victoria; Jin, Lee-Way; Chui, Helena C.; Coppola, Giovanni; Ringman, John M.

In: Journal of Alzheimer's Disease, Vol. 58, No. 4, 2017, p. 1035-1041.

Research output: Contribution to journalArticle

Liu, CY, Ohki, Y, Tomita, T, Osawa, S, Reed, BR, Jagust, W, Van Berlo, V, Jin, L-W, Chui, HC, Coppola, G & Ringman, JM 2017, 'Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease', Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1035-1041. https://doi.org/10.3233/JAD-161203
Liu, Collin Y. ; Ohki, Yu ; Tomita, Taisuke ; Osawa, Satoko ; Reed, Bruce R ; Jagust, William ; Van Berlo, Victoria ; Jin, Lee-Way ; Chui, Helena C. ; Coppola, Giovanni ; Ringman, John M. / Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. In: Journal of Alzheimer's Disease. 2017 ; Vol. 58, No. 4. pp. 1035-1041.
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abstract = "Background: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. Objective: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. Methods: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. Results: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aβ42 and decreased APP and Notch intracellular domain production in vitro. Conclusion: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aβ.",
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AU - Reed, Bruce R

AU - Jagust, William

AU - Van Berlo, Victoria

AU - Jin, Lee-Way

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AU - Ringman, John M.

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