Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy

Abstract

Abstract:The homozygous loss of the survival motor neuron 1 (SMN1) gene is the primary cause of spinal muscular atrophy (SMA), a neuromuscular degenerative disease. A genetically similar gene, SMN2, which is not functionally equivalent in all SMA patients, modifies the clinical SMA phenotypes. We analyzed the methylation levels of 4 CpG islands (CGIs) in SMN2 in 35 Chinese children with SMA by MassARRAY. We found that three CpG units located in CGI 1 (nucleotides (nt) −871, −735) and CGI 4 (nt +999) are significantly hypomethylated in SMA type III compared with type I or II children after receiving Bonferroni correction. In addition to the differentially methylated CpG unit of nt −871, the methylation level of the nt −290/−288/−285 unit was negatively correlated with the expression of SMN2 full-length transcripts (SMN2-fl). In addition, the methylation level at nt +938 was inversely proportional to the ratio of SMN2-fl and lacking exon 7 transcripts (SMN2-7, fl/7), and was not associated with the SMN2 transcript levels. Thus, we can conclude that SMN2 methylation may regulate the SMA disease phenotype by modulating its transcription.

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

“…Studies on the methylation level of different CpGs on the SMN2 genes revealed that hypomethylation was associated with reduced disease severity [ 92 ]. In fact, SMA type 3 exhibited a lower degree of methylation in the SMN2 gene compared to type 1 or 2 patients [ 93 ]. After profiling the methylation in SMA patients and healthy controls, Zheleznyakova et al identified differential degrees of methylation at CpG sites in the following genes; CHM Like Rab Escort Protein ( CHML ), Rho GTPase Activating Protein 22 ( ARHGAP22 ), Cytokinesis And Spindle Organization B ( CYTSB ), Cyclin Dependent Kinase 2 Associated Protein 1 ( CDK2AP1 ), and Solute Carrier Family 23 Member 2 ( SLC23A2 ) [ 94 ].…”

Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy

“…Studies suggest that epigenetic effects such as SMN2 methylation may regulate SMA disease phenotype by modulating its transcription (59–61). Genome wide methylation studies have determined differences in methylation patterns in certain genes, suggesting involvement of their proteins in pathogenesis of SMA (62).…”

“…Genome wide methylation studies have determined differences in methylation patterns in certain genes, suggesting involvement of their proteins in pathogenesis of SMA (62). Discordant sibling pairs with identical SMN genotypes, suggest that epigenetic modification may control individual variations in the SMN2 function (59).…”

Biology and clinical relevance of noncoding sno/scaRNAs

“…Spinal muscular atrophy (SMA) is a neuromuscular degenerative disorder in which motor neurons in the anterior horn of the spinal cord deteriorate and presents clinically as progressive muscle weakness with diminished or absent reflexes [72, 73]. Relatively common, SMA has an incidence rate of 1 in 11,000 live births [74].…”

“…Relatively common, SMA has an incidence rate of 1 in 11,000 live births [74]. This condition is due to the loss of the survival motor neuron 1 ( SMN1 ) gene, however, severity is determined by the gene, SMN2 [72]. Differing degrees of severity categorize the disorder into four types (I–IV), with SMA type I being the most severe and earliest onset and SMA type IV being the least severe and latest onset [72].…”