Dataset Information

Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis.

ABSTRACT: Mutations in the prion-like domain (PrLD) of hnRNPA1 and A2/B1 genes were recently identified in 2 families with inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis, and in ALS patients. These mutations were shown to increase the propensity of hnRNPA1 and A2/B1 proteins, which are TDP-43-binding partners, to self-aggregate. hnRNPA3 protein contains a similar PrLD and was recently described in the p62-positive/TDP-43-negative inclusions in affected tissues of C9orf72-mutated ALS/FTD patients. We screened hnRNPA1, A2/B1, and A3 genes in a cohort of 113 familial ALS (FALS) individuals without mutations in other known ALS-causative genes. We extended our analysis to 108 FALS with mutations in other ALS-associated genes and to 622 sporadic cases by screening specifically the PrLDs of hnRNPA1, A2/B1, and A3. We failed to find variants in each cohort. Our results suggest that mutations in hnRNPA1, A2/B1, and A3 genes are a rare finding in ALS.

SUBMITTER: Calini D

PROVIDER: S-EPMC6591723 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis.

Calini Daniela D Corrado Lucia L Del Bo Roberto R Gagliardi Stella S Pensato Viviana V Verde Federico F Corti Stefania S Mazzini Letizia L Milani Pamela P Castellotti Barbara B Bertolin Cinzia C Sorarù Gianni G Cereda Cristina C Comi Giacomo P GP D'Alfonso Sandra S Gellera Cinzia C Ticozzi Nicola N Landers John E JE Ratti Antonia A Silani Vincenzo V

Neurobiology of aging 20130702 11

Mutations in the prion-like domain (PrLD) of hnRNPA1 and A2/B1 genes were recently identified in 2 families with inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis, and in ALS patients. These mutations were shown to increase the propensity of hnRNPA1 and A2/B1 proteins, which are TDP-43-binding partners, to self-aggregate. hnRNPA3 protein contains a similar PrLD and was recently described in the p62-positive/TDP-43-nega ...[more]

PMID: 23827524

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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

Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis.

Publications

Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis.

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