Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy

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

doi:10.1016/j.gene.2012.12.109

Cited by 45 publications

(35 citation statements)

References 24 publications

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“…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%

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Genetic findings of Cypriot spinal muscular atrophy patients

et al. 2015

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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.

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Section: Discussionsupporting

confidence: 92%

“…GTF2H2 deletion in Type I patients presented as Genotype 1 and 4, found equally in 1/7 (14 %) patients. The extended deletion of Genotype 4 is commonly associated with the severe Type I phenotype and found at equivalent deletion rates (14 %) in Turkish, Chinese and European populations [17,21,26,27].…”

Section: Discussionmentioning

confidence: 99%

Genetic findings of Cypriot spinal muscular atrophy patients

et al. 2015

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“…The region of the human chromosome that encodes NAIP (5q13) has been described as highly variable2425 and rich in gene copy number variation. Consistent with its role in innate immunology, a higher copy number of the full NAIP gene has been shown to protect against Legionella pneumophila infection in human populations26; given its antiapoptostic role, it has also been inversely related with the clinical severity of SMA27.…”

mentioning

confidence: 83%

Neuronal apoptosis inhibitory protein (NAIP) localizes to the cytokinetic machinery during cell division

Abadía-Molina

Morón-Calvente

Baird

et al. 2017

Sci Rep

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The neuronal apoptosis inhibitory protein (NAIP) is a constituent of the inflammasome and a key component of the innate immune system. Here we use immunofluorescence to position NAIP within the cytokinetic apparatus, contiguous to chromosomal passenger complex (CPC), Centralspindlin, PRC1 and KIF4A. During metaphase, NAIP accumulates in the mitotic spindle poles and is shown in spindle microtubules; in anaphase NAIP is detected in the middle of the central spindle. At the end of cytokinesis, NAIP is localized in the outlying region of the stem body, the center of the intercellular bridge formed between daughter cells prior to cellular abscission. We also describe the sustained presence of NAIP mRNA and protein throughout the cell cycle with a significant increase observed in the G2/M phase. Consistent with a role for NAIP in cytokinesis, NAIP overexpression in HeLa cells promotes the acquisition of a multinuclear phenotype. Conversely, NAIP siRNA gene silencing results in an apoptotic lethal phenotype. Our confocal and super resolution stimulated-emission-depletion (STED) examination of mammalian cell cytokinesis demonstrate a potential new role for NAIP in addition to anti-apoptotic and innate immunology functions.

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“…Previous studies showed that expansion of the SMN1 deletion to NAIP, P44, and H4F5 is always associated with a severe phenotype, including early age of onset and early death. [37][38][39] Conversion of SMN1 to SMN2 40,41 results in increased SMN2 copy number and is inversely correlated with phenotype severity. Our recent report, 9 revealed that the median age onset is 1 month in SMA patients with SMN1-SMN2-NAIP genotype of 0-2-0, whereas in patients with 0-3-2 genotype were 8 months.…”

Section: Discussionmentioning

confidence: 99%

A rare variant (c.863G>T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy

Bai

Cao

et al. 2015

Eur J Hum Genet

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Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or mutation of SMN1 (survival motor neuron 1). SMN exon 7 splicing is regulated by a number of exonic and intronic regulatory sequences and the trans-factors that bind them. Variants located in or near these regulated regions should be evaluated to determine their effect on splicing. We identified the rare variant c.863G4T (r.835_*3del, p.Gly279Glufs*5) in exon 7 of SMN1 in three patients affected with type I or type II SMA. Most of the SMN1 transcripts exhibited complete loss of exon 7 in vivo. The ex vivo splicing assay demonstrated that the variant disrupts inclusion of exon 7 (~85%) in the SMN1 mRNA; replacement with various bases yielded a variety of splicing effects in SMN1 and SMN2 pre-mRNA. The c.863G4T (r.835_*3del, p.Gly279Glufs*5) variant is located in a region that includes binding sites for multiple splicing factors including Tra2β1. Thus, the variant disrupts Tra2β1 binding, but does not affect binding of hnRNP A1. These findings demonstrate how rare variants influence pre-mRNA splicing of SMN and reveal the functional influence of c.863G4T (r.835_*3del, p.Gly279Glufs*5) variant in patients with SMA.

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Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy

Cited by 45 publications

References 24 publications

Genetic findings of Cypriot spinal muscular atrophy patients

Genetic findings of Cypriot spinal muscular atrophy patients

Neuronal apoptosis inhibitory protein (NAIP) localizes to the cytokinetic machinery during cell division

A rare variant (c.863G>T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy

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