Genetic reports abstractNegative resultsMutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients
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.
References (15)
- et al.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
(2011) - et al.
Exome sequencing reveals VCP mutations as a cause of familial ALS
Neuron
(2010) - et al.
Amyotrophic lateral sclerosis
Lancet
(2011) - et al.
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Neuron
(2011) - et al.
Mutational analysis of VCP gene in familial amyotrophic lateral sclerosis
Neurobiol. Aging
(2012) - et al.
Mutation analysis of VCP in familial and sporadic amyotrophic lateral sclerosis
Neurobiol. Aging
(2012) - et al.
Clinical genetics of amyotrophic lateral sclerosis: what do we really know?
Nat. Rev. Neurol.
(2011)