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Dual Mechanism of a New SMN1 Variant (c.835G>C, p.Gly279Arg) by Interrupting Exon 7 Skipping and YG Oligomerization in Causation of Spinal Muscular Atrophy.
- Source :
-
Journal of molecular neuroscience : MN [J Mol Neurosci] 2021 Jan; Vol. 71 (1), pp. 112-121. Date of Electronic Publication: 2020 Aug 18. - Publication Year :
- 2021
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Abstract
- Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or subtle variant of survival motor neuron 1 (SMN1) gene. By multiplex ligation-dependent probe amplification, genomic sequencing, and T-A cloning on cDNA level, we identified one novel SMN1 subtle variant c.835G>C (p.Gly279Arg) in a non-homozygous patient with type 1 SMA. Full-length SMN1 (fl-SMN1) transcripts in the peripheral bloods of the patient were significantly decreased compared with those in healthy individuals and the carries (p < 0.05). And two fragments of SMN1 transcripts including fl-SMN1 and △7-SMN1 were observed by RT-PCR, which indicated Exon 7 skipping of SMN1 gene. To further evaluate its splicing effects on Exon 7, we performed ex vivo splicing analysis, which showed that the mutant mini gene with c.835G>C reduced Exon 7 inclusion to 54%. In addition, self-oligomerization between mutant SMN protein with the c.835G>C (p.Gly279Arg) and wild SMN was decreased in self-interaction assays. Our study clearly demonstrates that the c.835G>C (p.Gly279Arg) variant can lead to a decrease in fl-SMN1 transcripts by interrupting correct splicing of SMN1. What is more, the variant also affects SMN self-oligomerization via amino acid substitution from Gly to Arg at amino acid position of 279. This work presents the first evidence that it does exit double-hit events for the novel variant, which is crucial to understanding a severe SMA phenotype (type 1).
- Subjects :
- Base Sequence
Causality
Child, Preschool
Cloning, Molecular
DNA, Complementary genetics
Female
HEK293 Cells
Humans
Multiplex Polymerase Chain Reaction
RNA Splicing
RNA, Messenger blood
RNA, Messenger genetics
Reverse Transcriptase Polymerase Chain Reaction
Sequence Alignment
Sequence Homology, Amino Acid
Transfection
Amino Acid Sequence
Exons genetics
Mutation, Missense
Point Mutation
Spinal Muscular Atrophies of Childhood genetics
Survival of Motor Neuron 1 Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1559-1166
- Volume :
- 71
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of molecular neuroscience : MN
- Publication Type :
- Academic Journal
- Accession number :
- 32812185
- Full Text :
- https://doi.org/10.1007/s12031-020-01631-7