Extracellular pH change modulates the exon 7 splicing in SMN2 mRNA.
Spinal muscular atrophy (SMA) is caused by homozygous deletions/mutations of SMN1 gene. All SMA patients carry a nearly identical SMN2 gene. A nucleotide change in SMN2 results in exon 7 exclusion in the majority of SMN2 mRNA, thus producing low level of SMN protein. Extracellular pH change has been shown to modulate alternative splicing of several pre-mRNAs. In this study, we showed that extracellular pH change can also modulate SMN2 exon 7 splicing in SMA cells. Low extracellular pH enhances SMN2 exon 7 skipping, whereas high extracellular pH promotes its inclusion. Low extracellular pH also reduces SMN protein expression but increases hnRNP A1 expression. In addition, we tested whether intracellular pH-modulating genes could be the modifier of SMA in a SMA discordant family and found that the mRNA levels of ATP6V1B2 gene are significantly higher in two affected siblings than the unaffected one. In conclusion, our results suggest that extracellular pH change modulates SMN2 exon 7 splicing through regulation of hnRNP A1 expression in SMA cells.
Chen
Yi-Ching
YC
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Yuo
Chung-Yee
CY
Yang
Wen-Kuang
WK
Jong
Yuh-Jyh
YJ
Lin
Hui-Hua
HH
Chang
Ya-Sian
YS
Chang
Jan-Gowth
JG
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017398:Alternative Splicing; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D045604:Extracellular Fluid / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008214:Lymphocytes / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D055532:SMN Complex Proteins / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C489559:KHDRBS1 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein