Elsevier

Neurobiology of Aging

Volume 34, Issue 4, April 2013, Pages 1311.e1-1311.e2
Neurobiology of Aging

Genetic reports abstract
Negative results
Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients

https://doi.org/10.1016/j.neurobiolaging.2012.09.001Get rights and content

Abstract

Mutations in the profilin 1 (PFN1) gene, encoding a member of the profilin family of small actin-binding proteins, have been recently reported in patients with familial amyotrophic lateral sclerosis (ALS). In this study we aimed to determine the prevalence of PFN1 mutations by sequencing the coding region of this gene in a cohort of 94 familial ALS patients from France and Quebec. No mutations were identified in our cohort suggesting that PFN1 gene mutations are a very rare cause of familial ALS among patients with predominantly European ancestry.

Introduction

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by the progressive loss of motor neurons in the corticospinal tract, brainstem, and anterior horn cells of the spinal cord, which leads to muscle atrophy, progressive paralysis, and death (Kiernan, et al., 2011). ALS is mainly a sporadic disease, but 5% of ALS cases have a family history and show a Mendelian pattern of inheritance (Dion, et al., 2009; Hardiman, et al., 2011). These familial ALS (FALS) cases are clinically indistinguishable from sporadic ALS (SALS) cases. Interestingly, genetic studies of FALS cases have greatly contributed to our understanding of the molecular mechanisms underlying SALS cases because all genes identified in FALS have been also found mutated in SALS cases, although in a smaller percentage (Andersen and Al-Chalabi, 2011). The most common genes mutated in FALS are SOD1 (Rosen, et al., 1993), TARDBP (Kabashi, et al., 2008), FUS (Vance, et al., 2009), and the recently identified GGGGCC repeat expansion in the C9ORF72 gene (DeJesus-Hernandez, et al., 2011; Renton, et al., 2011). Other genes have been reported in FALS cases but they are very rare (Andersen and Al-Chalabi, 2011). Very recently, Wu and colleagues applied the exome sequencing approach to 2 large ALS families in which linkage analysis was previously performed to narrow the list of candidate causative genes in each family (Wu, et al., 2012). Only the profilin 1 (PFN1) gene was mutated in both families. Further sequencing of the PFN1 gene in a cohort of FALS cases led to the identification of 5 additional families with PFN1 mutations, which suggested a PFN1 mutation frequency of 1%–2% in FALS cases (Wu, et al., 2012). Here, we sought to assess the frequency of PFN1 mutations in a cohort of 94 FALS patients of French and French-Canadian origin with no mutations in previously known ALS-causative genes.

Section snippets

Methods

A total of 94 patients with familial ALS were recruited through clinics in France and Canada. Patients were diagnosed with possible, probable, or definite ALS as per El Escorial criteria. DNA samples were collected with the approval of the relevant institutional ethic boards and informed written consent was obtained from each participant. Mutations and expansions in the SOD1, TARDBP, FUS, and C9ORF72 genes were excluded in all FALS patients before this study. The three coding exons and flanking

Results

We performed a mutational analysis of the entire coding sequence of the PFN1 gene in a cohort of 94 patients with familial ALS with no mutations in the SOD1, TARDBP, FUS, and C9ORF72 genes. We identified 1 synonymous change (p.L112L) in 24 FALS patients. However, this silent mutation is likely to be a benign polymorphism because it was found in the NHLBI ESP Exome Variant Server and the dbSNP database. No other variant in the PFN1 gene was identified in our cohort of FALS patients.

Discussion

Recently, exome sequencing of 2 genetically unexplained large ALS families with a dominant mode of inheritance led to the identification of mutations in the PFN1 gene (Wu, et al., 2012). The PFN1 gene encodes a 140-amino acid protein that plays an important role in actin dynamics by regulating actin polymerization (Mockrin and Korn, 1980). Five additional PFN1 mutations were identified after its sequencing in 272 FALS cases. These findings suggested that PFN1 mutations account for 1%–2% of all

Disclosure statement

The authors declare no conflicts of interest exist.

DNA samples were collected with the approval of the relevant institutional ethic boards and informed written consent was obtained from each participant.

Acknowledgements

The authors thank the subjects and their parents for their participating in this study. H.D. is supported by a postdoctoral fellowship from the ALS Society of Canada and the CIHR. G.A.R. holds a Canada Research Chair in Genetics of the Nervous System and the Jeanne et J-Louis-Lévesque in Genetics of Brain Diseases.

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