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Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Volume 19, 2018 - Issue 1-2
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Original Article

Increase in DNA methylation in patients with amyotrophic lateral sclerosis carriers of not fully penetrant SOD1 mutations

Fabio CoppedèDepartment of Translational Research and New Technologies in Medicine and Surgery, Section of Medical Genetics, University of Pisa, Pisa, Italy, Correspondence[email protected]
,
Andrea StoccoroDepartment of Translational Research and New Technologies in Medicine and Surgery, Section of Medical Genetics, University of Pisa, Pisa, Italy, ;Doctoral School in Genetics Oncology and Clinical Medicine, Department of Medical Biotechnologies, University of Siena, Siena, Italy,
,
Lorena MoscaMedical Genetics Unit, Department of Laboratory Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, and
,
Roberta GalloDepartment of Translational Research and New Technologies in Medicine and Surgery, Section of Medical Genetics, University of Pisa, Pisa, Italy,
,
Claudia TarlariniMedical Genetics Unit, Department of Laboratory Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, and
,
Christian LunettaNEuroMuscular Omnicentre (NEMO), ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
,
Alessandro MarocchiMedical Genetics Unit, Department of Laboratory Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, and
,
Lucia MiglioreDepartment of Translational Research and New Technologies in Medicine and Surgery, Section of Medical Genetics, University of Pisa, Pisa, Italy,
&
Silvana PencoMedical Genetics Unit, Department of Laboratory Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, and
show all
Pages 93-101 | Received 19 May 2017, Accepted 08 Aug 2017, Published online: 01 Sep 2017
 
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Abstract

Objective: More than 180 different superoxide dismutase 1 (SOD1) mutations have been described to date in amyotrophic lateral sclerosis (ALS) patients, including not completely penetrant ones leading to phenotypic heterogeneity among carriers. We collected DNA samples from five ALS families with not fully penetrant SOD1 mutations (p.Asn65Ser, p.Gly72Ser, p.Gly93Asp, and p.Gly130_Glu133del) searching for epigenetic differences among ALS patients, asymptomatic/paucisymptomatic carriers and non-carrier family members.

Methods: Global DNA methylation levels (5-methylcytosine levels) were determined in blood DNA samples with an enzyme-linked immunosorbent assay (ELISA), and the methylation analysis of SOD1, FUS, TARDBP and C9orf72 genes was performed using Methylation-Sensitive High-Resolution Melting (MS-HRM) technique.

Results: Global DNA methylation levels were significantly higher in blood DNA of ALS patients than in asymptomatic/paucisymptomatic carriers or family members non-carriers of SOD1 mutations, and a positive correlation between global DNA methylation levels and disease duration (months) was observed. SOD1, FUS, TARDBP and C9orf72 gene promoters were demethylated in all subjects.

Conclusions: The present study suggests that global changes in DNA methylation might contribute to the ALS phenotype in carriers of not fully penetrant SOD1 mutations, thus reinforcing the role of epigenetic factors in modulating the phenotypic expression of the disease.

Acknowledgements

This work was supported by a grant from “ASSOCIAZIONE IO CORRO CON GIOVANNI”, www.iocorrocongiovanni.org; [email protected]; Paina di Giussano – Via IV Novembre 20 - c/o Centro Associativo “Generazioni”.

Declaration of interest

The authors declare that they have no competing interests.

Supplementary available online

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