Abstract

Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations of the survival motor neuron 1 (SMN1) gene. SMN2, a paralogous gene to SMN1, can partially compensate for the loss of SMN1. On the basis of age at onset, highest motor function and SMN2 copy numbers, childhood-onset SMA can be divided into three types (SMA I-III). An inverse correlation was observed between SMN2 copies and the differential phenotypes of SMA. Interestingly, this correlation is not always absolute. Using SMA induced pluripotent stem cells (iPSCs), we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons (pMNs) and γ-aminobutyric acid (GABA) neurons. Moreover, the significant differences of SMN expression level between SMA III (3 copies of SMN2) and SMA I (2 copies of SMN2) were observed only in pMNs culture, but not in GABA neurons or iPSCs. From these findings, we further discovered that the neurite outgrowth was suppressed in both SMA III and SMA I derived MNs. Meanwhile, the significant difference of neurite outgrowth between SMA III and SMA I group was also found in long-term cultures. However, significant hyperexcitability was showed only in SMA I derived mature MNs, but not in SMA III group. Above all, we propose that SMN protein is a major factor of phenotypic modifier. Our data may provide a new insight into recognition for differential phenotypes of SMA disease.

Highlights

  • Spinal muscular atrophy (SMA) is a devastating disorder associated with selective degeneration of spinal motor neurons (MNs), resulting in progressive muscle atrophy, generalized weakness and often death [1]

  • Using SMA induced pluripotent stem cells, we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons and γ-aminobutyric acid (GABA) neurons

  • Mutation screening with genomic DNA from the urine cells by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex ligation-dependent probe amplification (MLPA) showed homozygous deletion of survival motor neuron 1 (SMN1) and three copies of survival motor neuron 2 (SMN2), Figure 1: SMN gene mutation screening of cell lines from the three individuals

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Summary

Introduction

Spinal muscular atrophy (SMA) is a devastating disorder associated with selective degeneration of spinal motor neurons (MNs), resulting in progressive muscle atrophy, generalized weakness and often death [1]. It is one of the leading known genetic cause of infant mortality, affecting 1 in 6000 to 10 000 infants [2]. Induced pluripotent stem cells (iPSCs) from SMA patients have been generated to study the motor neuron phenotypes in cell cultures [10,11,12,13,14,15]. The MN differentiation protocols they employed were time-consuming and low-efficient, which limit SMA disease modeling studies

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