Dataset Information

SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

ABSTRACT: IMPORTANCE:Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. OBJECTIVE:To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. DESIGN:A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. SETTING:Primary care or referral center. PARTICIPANTS:An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. MAIN OUTCOMES AND MEASURES:Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. RESULTS:We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. CONCLUSIONS AND RELEVANCE:Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

SUBMITTER: Le Ber I

PROVIDER: S-EPMC4199096 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

Le Ber Isabelle I Camuzat Agnès A Guerreiro Rita R Bouya-Ahmed Kawtar K Bras Jose J Nicolas Gael G Gabelle Audrey A Didic Mira M De Septenville Anne A Millecamps Stéphanie S Lenglet Timothée T Latouche Morwena M Kabashi Edor E Campion Dominique D Hannequin Didier D Hardy John J Brice Alexis A

JAMA neurology 20131101 11

<h4>Importance</h4>Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD.<h4>Objective</h4>To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients.<h4>Design</h4>A SQSTM1 mutation was first identifie ...[more]

PMID: 24042580

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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

SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

Publications

SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

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