Dataset Information

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

SUBMITTER: Williams KL

PROVIDER: S-EPMC4835537 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Williams Kelly L KL Topp Simon S Yang Shu S Smith Bradley B Fifita Jennifer A JA Warraich Sadaf T ST Zhang Katharine Y KY Farrawell Natalie N Vance Caroline C Hu Xun X Chesi Alessandra A Leblond Claire S CS Lee Albert A Rayner Stephanie L SL Sundaramoorthy Vinod V Dobson-Stone Carol C Molloy Mark P MP van Blitterswijk Marka M Dickson Dennis W DW Petersen Ronald C RC Graff-Radford Neill R NR Boeve Bradley F BF Murray Melissa E ME Pottier Cyril C Don Emily E Winnick Claire C McCann Emily P EP Hogan Alison A Daoud Hussein H Levert Annie A Dion Patrick A PA Mitsui Jun J Ishiura Hiroyuki H Takahashi Yuji Y Goto Jun J Kost Jason J Gellera Cinzia C Gkazi Athina Soragia AS Miller Jack J Stockton Joanne J Brooks William S WS Boundy Karyn K Polak Meraida M Muñoz-Blanco José Luis JL Esteban-Pérez Jesús J Rábano Alberto A Hardiman Orla O Morrison Karen E KE Ticozzi Nicola N Silani Vincenzo V de Belleroche Jacqueline J Glass Jonathan D JD Kwok John B J JB Guillemin Gilles J GJ Chung Roger S RS Tsuji Shoji S Brown Robert H RH García-Redondo Alberto A Rademakers Rosa R Landers John E JE Gitler Aaron D AD Rouleau Guy A GA Cole Nicholas J NJ Yerbury Justin J JJ Atkin Julie D JD Shaw Christopher E CE Nicholson Garth A GA Blair Ian P IP

Nature communications 20160415

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCN ...[more]

PMID: 27080313

Similar Datasets

Project description:Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.

Dataset Information

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Publications

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets