title: Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity.
abstract: Spinal muscular atrophy (SMA) is a monogenic disorder that is subdivided into four different types and caused by survival motor neuron gene 1 (SMN1) deletion. Discordant cases of SMA suggest that there exist additional severity modifying factors, apart from the SMN2 gene copy number. Here we performed the first genome-wide methylation profiling of SMA patients and healthy individuals to study the association of DNA methylation status with the severity of the SMA phenotype. We identified strong significant differences in methylation level between SMA patients and healthy controls in CpG sites close to the genes CHML, ARHGAP22, CYTSB, CDK2AP1 and SLC23A2. Interestingly, the CHML and ARHGAP22 genes are associated with the activity of Rab and Rho GTPases, which are important regulators of vesicle formation, actin dynamics, axonogenesis, processes that could be critical for SMA development. We suggest that epigenetic modifications may influence the severity of SMA and that these novel genetic positions could prove to be valuable biomarkers for the understanding of SMA pathogenesis.
authors.affiliation: Faculty of Biology and Soil Science, Saint-Petersburg State University, Saint-Petersburg, Russia. galinazheleznyakova@gmail.com
authors.forename: Galina Y
authors.initials: GY
authors.lastname: Zheleznyakova
authors.forename: Sarah
authors.initials: S
authors.lastname: Voisin
authors.forename: Anton V
authors.initials: AV
authors.lastname: Kiselev
authors.forename: Markus
authors.initials: M
authors.lastname: Sällman Almén
authors.forename: Miguel J
authors.initials: MJ
authors.lastname: Xavier
authors.forename: Marianna A
authors.initials: MA
authors.lastname: Maretina
authors.forename: Lyudmila I
authors.initials: LI
authors.lastname: Tishchenko
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Baranov
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D063990:Gene Ontology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D055815:Young Adult; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020691:rab GTP-Binding Proteins; D020741:rho GTP-Binding Proteins