Modification of phenotype by SMN2 copy numbers in two Chinese families with SMN1 deletion in two continuous generations

Chen, Wan‐Jin; He, J.; Zhang, Qijie; Lin, Qi-Fang; Chen, Ya-Fang; Lin, Xia; Lin, Min; Murong, Shen-Xing; Wang, Ning

doi:10.1016/j.cca.2012.07.020

Cited by 5 publications

(3 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our studied population, all patients with three SMN2 copies presented with milder types II and III phenotypes whereas all severe Type I carried two copies. Our data are in concordance with the reported inverse relationship between SMN2 copy number and disease severity [9,17,[27][28][29]. However, our results showed that phenotype cannot be predicted by the SMN2 copy number.…”

Section: Discussionsupporting

confidence: 92%

Genetic findings of Cypriot spinal muscular atrophy patients

et al. 2015

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families.

show abstract

Section: Discussionsupporting

confidence: 92%

Genetic findings of Cypriot spinal muscular atrophy patients

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Since 10% of the SMN2 gene product is full-length SMN protein, SMN2 expression may compensate for insufficient production of mutated SMN1 . Indeed, the SMN2 copy number correlates negatively with disease severity [ 7 , 8 ]. Thus, SMN2 is considered as an important SMA disease modifier to be a potential target for SMA treatment.…”

Section: Introductionmentioning

confidence: 99%

An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy

et al. 2016

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is an inherited neuromuscular disease resulting from a recessive mutation in the SMN1 gene. This disease affects multiple organ systems with varying degrees of severity. Exploration of the molecular pathological changes occurring in different cell types in SMA is crucial for developing new therapies. This study collected 39 human microarray datasets from ArrayExpress and GEO databases to build an integrative transcriptomic analysis for recognizing novel SMA targets. The transcriptomic analysis was conducted through combining weighted correlation network analysis (WGCNA) for gene module detection, gene set enrichment analysis (GSEA) for functional categorization and filtration, and Cytoscape (visual interaction gene network analysis) for target gene identification. Seven novel target genes (Bmp4, Serpine1, Gata6, Ptgs2, Bcl2, IL6 and Cntn1) of SMA were revealed, and are all known in the regulation of TNFα for controlling neural, cardiac and bone development. Sequentially, the differentially expressed patterns of these 7 target genes in mouse tissues (e.g., spinal cord, heart, muscles and bone) were validated in SMA mice of different severities (pre-symptomatic, mildly symptomatic, and severely symptomatic). In severely symptomatic SMA mice, TNFα was up-regulated with attenuation of Bmp4 and increase of Serpine1 and Gata6 (a pathway in neural and cardiac development), but not in pre-symptomatic and mildly symptomatic SMA mice. The severely symptomatic SMA mice also had the elevated levels of Ptgs2 and Bcl2 (a pathway in skeletal development) as well as IL6 and Cntn1 (a pathway in nervous system development). Thus, the 7 genes identified in this study might serve as potential target genes for future investigations of disease pathogenesis and SMA therapy.

show abstract

“…High variability of clinical courses of SMA patients indicates that disease manifestation is apparently dependent on modifying factors. By now, SMN2 gene copy number can contribute as supplementary criterion for SMA severity determination, but its prediction accuracy is not absolute [38, 49, 59, 210]. Detection of additional modifiers on the early stages of disease development can make the prognosis of clinical course more precise.…”

Section: Resultsmentioning

confidence: 99%

Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates

Maretina

Zheleznyakova

Lanko

et al. 2018

View full text Add to dashboard Cite

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by mutations in the SMN1 gene. Being a monogenic disease, it is characterized by high clinical heterogeneity. Variations in penetrance and severity of symptoms, as well as clinical discrepancies between affected family members can result from modifier genes influence on disease manifestation. SMN2 gene copy number is known to be the main phenotype modifier and there is growing evidence of additional factors contributing to SMA severity. Potential modifiers of spinal muscular atrophy can be found among the wide variety of different factors, such as multiple proteins interacting with SMN or promoting motor neuron survival, epigenetic modifications, transcriptional or splicing factors influencing SMN2 expression. Study of these factors enables to reveal mechanisms underlying SMA pathology and can have pronounced clinical application.

show abstract

Modification of phenotype by SMN2 copy numbers in two Chinese families with SMN1 deletion in two continuous generations

Cited by 5 publications

References 32 publications

Genetic findings of Cypriot spinal muscular atrophy patients

Genetic findings of Cypriot spinal muscular atrophy patients

An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy

Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates

Contact Info

Product

Resources

About