TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism

Estrella Gomez-Tortosa; Yalda  Baradaran-Heravi; Lubina Dillen; Nila Roy Choudhury; Pablo Agüero Rabes; Julián  Pérez-Pérez; Cemile  Kocoglu; M. José Sainz; Alicia Ruiz  González; Raquel  Téllez; Lucía  Cremades-Jimeno; Blanca  Cárdaba; Christine Van  Broeckhoven; Gracjan Michlewski; Julie  van der Zee

doi:10.1002/alz.12913

TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism

Estrella Gomez-Tortosa, Yalda Baradaran-Heravi, Lubina Dillen, Nila Roy Choudhury, Pablo Agüero Rabes, Julián Pérez-Pérez, Cemile Kocoglu, M. José Sainz, Alicia Ruiz González, Raquel Téllez, Lucía Cremades-Jimeno, Blanca Cárdaba, Christine Van Broeckhoven, Gracjan Michlewski, Julie van der Zee

Research output: Contribution to journal › Article › peer-review

Abstract

INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity
for gene identification studies.
METHODS: We present the phenotype and whole-exome sequencing (WES) study of an
autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases
and controls (n=3712). Western blotting was conducted of the wild-type and mutant protein of
the final candidate.
RESULTS: Age at disease onset was 60 years (range 56-63). The phenotype comprised mixed
amnestic and behavioral features, and parkinsonism. CSF and plasma biomarkers, and a PETamyloid study suggested AD. WES and the segregation pattern pointed to a nonsense mutation
in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the
cohorts studied. Protein studies supported a loss-of-function mechanism.
DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis.
Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of
neurodegenerative diseases

Original language	English
Journal	Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Early online date	28 Dec 2022
DOIs	https://doi.org/10.1002/alz.12913
Publication status	E-pub ahead of print - 28 Dec 2022

Keywords / Materials (for Non-textual outputs)

early-onset autosomal dominant dementia
Alzheimer’s disease
TRIM25
E3 ubiquitin ligase
family-based whole-exome sequencing study

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ADJ-D-22-00618_R1Accepted author manuscript, 3.28 MBLicence: Creative Commons: Attribution (CC-BY)
Alzheimer s Dementia - 2022 - G mez‐Tortosa - TRIM25 mutation p C168 coding for an E3 ubiquitin ligase is a cause ofFinal published version, 870 KBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Cite this

Gomez-Tortosa, E., Baradaran-Heravi, Y., Dillen, L., Roy Choudhury, N., Rabes, P. A., Pérez-Pérez, J., Kocoglu, C., José Sainz, M., González, A. R., Téllez, R., Cremades-Jimeno, L., Cárdaba, B., Broeckhoven, C. V., Michlewski, G., & van der Zee, J. (2022). TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. Advance online publication. https://doi.org/10.1002/alz.12913

@article{5f0972f4967944b3b4a512a4c61978d9,

title = "TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism",

abstract = "INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies.METHODS: We present the phenotype and whole-exome sequencing (WES) study of anautosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n=3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate.RESULTS: Age at disease onset was 60 years (range 56-63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. CSF and plasma biomarkers, and a PETamyloid study suggested AD. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism. DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases",

keywords = "early-onset autosomal dominant dementia, Alzheimer{\textquoteright}s disease, TRIM25, E3 ubiquitin ligase, family-based whole-exome sequencing study",

author = "Estrella Gomez-Tortosa and Yalda Baradaran-Heravi and Lubina Dillen and {Roy Choudhury}, Nila and Rabes, {Pablo Ag{\"u}ero} and Juli{\'a}n P{\'e}rez-P{\'e}rez and Cemile Kocoglu and {Jos{\'e} Sainz}, M. and Gonz{\'a}lez, {Alicia Ruiz} and Raquel T{\'e}llez and Luc{\'i}a Cremades-Jimeno and Blanca C{\'a}rdaba and Broeckhoven, {Christine Van} and Gracjan Michlewski and {van der Zee}, Julie",

year = "2022",

month = dec,

day = "28",

doi = "10.1002/alz.12913",

language = "English",

journal = "Alzheimer's & Dementia: The Journal of the Alzheimer's Association",

issn = "1552-5260",

publisher = "Wiley",

}

Gomez-Tortosa, E, Baradaran-Heravi, Y, Dillen, L, Roy Choudhury, N, Rabes, PA, Pérez-Pérez, J, Kocoglu, C, José Sainz, M, González, AR, Téllez, R, Cremades-Jimeno, L, Cárdaba, B, Broeckhoven, CV, Michlewski, G & van der Zee, J 2022, 'TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism', Alzheimer's & Dementia: The Journal of the Alzheimer's Association. https://doi.org/10.1002/alz.12913

TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism. / Gomez-Tortosa, Estrella; Baradaran-Heravi, Yalda; Dillen, Lubina et al.
In: Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 28.12.2022.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism

AU - Gomez-Tortosa, Estrella

AU - Baradaran-Heravi, Yalda

AU - Dillen, Lubina

AU - Roy Choudhury, Nila

AU - Rabes, Pablo Agüero

AU - Pérez-Pérez, Julián

AU - Kocoglu, Cemile

AU - José Sainz, M.

AU - González, Alicia Ruiz

AU - Téllez, Raquel

AU - Cremades-Jimeno, Lucía

AU - Cárdaba, Blanca

AU - Broeckhoven, Christine Van

AU - Michlewski, Gracjan

AU - van der Zee, Julie

PY - 2022/12/28

Y1 - 2022/12/28

N2 - INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies.METHODS: We present the phenotype and whole-exome sequencing (WES) study of anautosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n=3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate.RESULTS: Age at disease onset was 60 years (range 56-63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. CSF and plasma biomarkers, and a PETamyloid study suggested AD. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism. DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases

AB - INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies.METHODS: We present the phenotype and whole-exome sequencing (WES) study of anautosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n=3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate.RESULTS: Age at disease onset was 60 years (range 56-63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. CSF and plasma biomarkers, and a PETamyloid study suggested AD. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism. DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases

KW - early-onset autosomal dominant dementia

KW - Alzheimer’s disease

KW - TRIM25

KW - E3 ubiquitin ligase

KW - family-based whole-exome sequencing study

U2 - 10.1002/alz.12913

DO - 10.1002/alz.12913

M3 - Article

SN - 1552-5260

JO - Alzheimer's & Dementia: The Journal of the Alzheimer's Association

JF - Alzheimer's & Dementia: The Journal of the Alzheimer's Association

ER -

Gomez-Tortosa E, Baradaran-Heravi Y, Dillen L, Roy Choudhury N, Rabes PA, Pérez-Pérez J et al. TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 2022 Dec 28. Epub 2022 Dec 28. doi: 10.1002/alz.12913

TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism

Abstract

Keywords / Materials (for Non-textual outputs)

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