Functional Analyses of Two Novel <i>LRRK2</i> Pathogenic Variants in Familial Parkinson′s Disease

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Abstract

Background

Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson's disease. However, only seven variants have been confirmed to be pathogenic.

Objectives

We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing.

Methods

We transiently expressed wild‐type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK‐293 T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins.

Results

The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity.

Conclusions

We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson's disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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Most cited references 34

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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The mutational constraint spectrum quantified from variation in 141,456 humans

Konrad J. Karczewski, Laurent C. Francioli, Grace Tiao … (2021)

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

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MDS clinical diagnostic criteria for Parkinson's disease.

Ronald Postuma, Daniela Berg, Matthew Stern … (2015)

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

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Author and article information

Contributors

Marie‐Christine Chartier‐Harlin:

ORCID: https://orcid.org/0000-0001-6416-6526

marie-christine.chartier-harlin@inserm.fr

Jean‐Marc Taymans:

ORCID: https://orcid.org/0000-0001-5503-5524

jean-marc.taymans@inserm.fr

Vincent Huin:

ORCID: https://orcid.org/0000-0001-8201-5406

vincent.huin@inserm.fr

Journal

Journal ID (nlm-ta): Mov Disord

Journal ID (iso-abbrev): Mov Disord

Journal ID (doi): 10.1002/(ISSN)1531-8257

Journal ID (publisher-id): MDS

Title: Movement Disorders

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 0885-3185

ISSN (Electronic): 1531-8257

Publication date (Electronic): 16 June 2022

Publication date (Print): August 2022

Volume: 37

Issue: 8 ( doiID: 10.1002/mds.v37.8 )

Pages: 1761-1767

Affiliations

[ ¹ ] University of Lille, Inserm, CHU Lille, U1172—LilNCog (JPARC)—Lille Neuroscience & Cognition Lille France

[ ² ] University of Lille, Inserm, CHU Lille, Expert Center for Parkinson's Disease Lille France

[ ³ ] Department of Neurology and Expert Center for Parkinson's Disease Amiens University Hospital, CHU Amiens‐Picardie Amiens France

[ ⁴ ] University of Lille, CNRS, Inserm, CHU Lille, UMR9020‐U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies Lille France

[ ⁵ ] Department of Neurology AZ Sint‐Lucas Bruges Belgium

[ ⁶ ] Department of Neurology University Hospitals Leuven Leuven Belgium

[ ⁷ ] Laboratory for Parkinson Research, Department of Neurosciences KU Leuven Leuven Belgium

[ ⁸ ] University of Lille, Inserm, CHU Lille, Department of Toxicology and Genopathies UF Neurobiology Lille France

Author notes

[*] [* ] Correspondence to: Dr. Vincent Huin, Lille Neuroscience & Cognition, Bâtiment Biserte, 1 Place de Verdun, F‐59045, Lille, France; E‐mail: vincent.huin@ 123456inserm.fr

Dr. Marie‐Christine, CHARTIER‐HARLIN Lille Neuroscience & Cognition, Bâtiment Biserte, 1 Place de Verdun, F‐59045, Lille, France; E‐mail: marie-christine.chartier-harlin@ 123456inserm.fr

Dr. Jean‐Marc, TAYMANS Lille Neuroscience & Cognition, Bâtiment Biserte, 1 Place de Verdun, F‐59045, Lille, France. E‐mail: jean-marc.taymans@ 123456inserm.fr

[†]

Marie‐Christine Chartier‐Harlin and Jean‐Marc Taymans contributed equally to this work.

Author information

Ilda Coku https://orcid.org/0000-0003-2622-6350

Eugénie Mutez https://orcid.org/0000-0002-5947-0432

Liesel Goveas https://orcid.org/0000-0003-0925-5870

Mélissa Tir https://orcid.org/0000-0001-9147-5519

Romain Magnez https://orcid.org/0000-0002-1882-8469

Xavier Thuru https://orcid.org/0000-0002-0998-4160

Wim Vandenberghe https://orcid.org/0000-0002-9758-5062

Luc Buée https://orcid.org/0000-0002-6261-4230

Luc Defebvre https://orcid.org/0000-0002-5325-195X

Bernard Sablonnière https://orcid.org/0000-0003-0384-4076

Marie‐Christine Chartier‐Harlin https://orcid.org/0000-0001-6416-6526

Jean‐Marc Taymans https://orcid.org/0000-0001-5503-5524

Vincent Huin https://orcid.org/0000-0001-8201-5406

Article

Publisher ID: MDS29124

DOI: 10.1002/mds.29124

PMC ID: 9543145

PubMed ID: 35708213

SO-VID: 3b028380-4f0c-4897-9444-2017c5543068

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 20 April 2022

Date received : 03 December 2021

Date accepted : 13 May 2022

Page count

Figures: 2, Tables: 0, Pages: 17, Words: 4540

Funding

Funded by: Agence Nationale de la Recherche , doi 10.13039/501100001665;

Award ID: ANR‐16‐CE16‐0012‐02 MeTDePaDi

Award ID: ANR‐20‐CE16‐0008 Synapark

Award ID: ANR‐21‐CE16‐0003‐01 PARK‐PEP

Funded by: Association France Alzheimer , doi 10.13039/501100003750;

Funded by: Association France Parkinson , doi 10.13039/501100008211;

Award ID: R16008

Funded by: Centre hospitalier régional universitaire de Lille , doi 10.13039/501100005261;

Funded by: Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease , doi 10.13039/100015867;

Funded by: Fondation de France , doi 10.13039/501100004431;

Award ID: Maladie de Parkinson

Award ID: R19199EK

Funded by: Institut National de la Santé et de la Recherche Médicale , doi 10.13039/501100001677;

Funded by: Michael J. Fox Foundation for Parkinson's Research , doi 10.13039/100000864;

Award ID: 10255.03

Award ID: 12938.04

Award ID: 6709.03

Funded by: Association des Aidants et Malades à Corps de Lewy (A2MCL) charity

Custom metadata

source-schema-version-number 2.0

cover-date August 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.0 mode:remove_FC converted:07.10.2022

ScienceOpen disciplines: Medicine

Keywords: parkinson's disease,lrrk2,mutation,kinase,genetics

Data availability:

ScienceOpen disciplines: Medicine

Keywords: parkinson's disease, lrrk2, mutation, kinase, genetics

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Functional Analyses of Two Novel LRRK2 Pathogenic Variants in Familial Parkinson′s Disease

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Abstract

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Most cited references 34

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

The mutational constraint spectrum quantified from variation in 141,456 humans

MDS clinical diagnostic criteria for Parkinson's disease.

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