Abstract
Cerebral palsy (CP) is a group of non-progressive motor impairment syndromes that are secondary to brain injury in the early stages of brain development. Numerous etiologies and risk factors of CP have been reported, and genetic contributions have recently been identified. Autophagy has an important role in brain development and pathological process, and autophagy-related gene 7 (ATG7) is essential for autophagosome biogenesis. The purpose of this study was to investigate the genetic association between ATG7 gene single nucleotide polymorphisms (SNPs) and CP in Han Chinese children. Six SNPs (rs346078, rs1470612, rs11706903, rs2606750, rs2594972, and rs4684787) were genotyped in 715 CP patients and 658 healthy controls using the MassArray platform. Plasma ATG7 protein was determined in 73 CP patients and 79 healthy controls. The differences in the allele and genotype frequencies of the rs1470612 and rs2594972 SNPs were determined between the CP patients and controls (pallele = 0.02 and 0.0004, pgenotype = 0.044 and 0.0012, respectively). Subgroup analysis revealed a more significant association of rs1470612 (pallele = 0.004, pgenotype = 0.0036) and rs2594972 (pallele = 0.0004, pgenotype < 0.0001) with male CP, and more significant differences in allele and genotype frequencies were also noticed between CP patients with spastic diplegia and controls for rs1470612 (pallele = 0.0024, pgenotype = 0.008) and rs2594972 (pallele < 0.0001, pgenotype = 0.006). The plasma ATG7 level was higher in CP patients compared to the controls (10.58 ± 0.85 vs. 8.18 ± 0.64 pg/mL, p = 0.024). The luciferase reporter gene assay showed that the T allele of rs2594972 SNP could significantly increase transcriptional activity of the ATG7 promoter compared to the C allele (p = 0.009). These findings suggest that an association exists between genetic variants of ATG7 and susceptibility to CP, which provides novel evidence for the role of ATG7 in CP and contributes to our understanding of the molecular mechanisms of this neurodevelopmental disorder.
Highlights
Cerebral palsy (CP) is a group of permanent neurological disabilities that manifest during early childhood and affect movement and posture, with a prevalence of 2–3/1000 live births (MacLennan et al, 2015; Nelson and Blair, 2015; Lim, 2016)
We performed an association analysis using CP case-control groups, and significant differences were observed in both allele and genotype frequencies between the total CP patients (n = 715) and controls (n = 658) for rs1470612 (OR = 1.281, 95% CI = 1.077– 1.523, pallele = 0.02, pgenotype = 0.044 after SNPSpD correction) and
odd ratios (ORs), odds ratio; CI, confidence interval. This case-control study showed that both the allele frequency and genotype frequency of the rs1470612 and rs2594972 single nucleotide polymorphisms (SNPs) in the autophagy-related gene 7 (ATG7) gene were associated with CP, and a stronger correlation was found in spastic diplegia and male subgroups, indicating that ATG7 might have an important influence in severe types of CP and that there might be sex-related differences
Summary
Cerebral palsy (CP) is a group of permanent neurological disabilities that manifest during early childhood and affect movement and posture, with a prevalence of 2–3/1000 live births (MacLennan et al, 2015; Nelson and Blair, 2015; Lim, 2016). Autophagy is a highly conserved cellular process that delivers damaged proteins and organelles to lysosomes for digestion (Rubinsztein et al, 2012), and autophagy is involved in intracellular quality control, starvation adaptation, development and aging (Oppenheim et al, 2008) It plays an important role in the process of normal brain development and defense against pathological processes (Komatsu et al, 2006; Oppenheim et al, 2008; Yamamoto and Yue, 2014), and autophagy deficiency or excessive activation can induce cell death and lead to pathological conditions (Zhu et al, 2006; Xie et al, 2016). It has been shown that Atg plays a vital role in the development of axons and dendrites and in synapse maturation processes (Kim et al, 2016), and selective deletion of Atg revealed its roles in adipogenesis, gluconeogenesis, and lipid metabolism (Rubio-Gonzalez et al, 2015)
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