Dataset Information

A Variant of the Autophagy-Related 5 Gene Is Associated with Child Cerebral Palsy.

ABSTRACT: Cerebral palsy (CP) is a major cause of childhood disability in developed and developing countries, but the pathogenic mechanisms of CP development remain largely unknown. Autophagy is a highly conserved cellular self-digestion of damaged organelles and dysfunctional macromolecules. Growing evidence suggests that autophagy-related gene 5 (ATG5)-dependent autophagy is involved in neural development, neuronal differentiation, and neurological degenerative diseases. The aim of this study was to analyze ATG5 protein expression and gene polymorphisms in Chinese patients with CP and to evaluate the importance of ATG5 in the development of CP. Five polymorphisms from different regions of the ATG5 gene (rs510432, rs3804338, rs573775, rs2299863, and rs6568431) were analyzed in 715 CP patients and 658 controls using MassARRAY. Of these, 58 patients and 56 controls were selected for measurement of plasma ATG5 level using ELISA. The relevance of disease-associated SNPs was evaluated using the SHEsis program. We identified a significant association between rs6568431 and CP (OR = 1.388, 95% CI = 1.173~1.643, Pallele = 0.0005, Pgenotype = 0.0015). Subgroup analysis showed a highly significant association of rs6568431 with spastic CP (n = 468, OR = 1.511, 95% CI = 1.251~1.824, Pallele = 8.50e-005, Pgenotype = 1.57e-004) and spastic quadriplegia (OR = 1.927, 95% CI = 1.533~2.421, Pallele = 7.35e-008, Pgenotype = 3.24e-009). Furthermore, mean plasma ATG5 levels were lower in CP patients than in controls, and individuals carrying the AA genotype of rs6568431 that was positively associated with CP had lower plasma ATG5 levels (P < 0.05). This study demonstrated an association of an ATG5 gene variant and low level of ATG5 protein with CP, and stronger associations with severe clinical manifestations were identified. Our results provide novel evidence for a role of ATG5 in CP and shed light on the molecular mechanisms underlying this neurodevelopmental disorder.

SUBMITTER: Xu J

PROVIDER: S-EPMC5741640 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A Variant of the Autophagy-Related 5 Gene Is Associated with Child Cerebral Palsy.

Xu Jianhua J Xia Lei L Shang Qing Q Du Jing J Zhu Dengna D Wang Yangong Y Bi Dan D Song Juan J Ma Caiyun C Gao Chao C Zhang Xiaoli X Sun Yanyan Y Zhu Liping L Wang Xiaoyang X Zhu Changlian C Xing Qinghe Q

Frontiers in cellular neuroscience 20171218

Cerebral palsy (CP) is a major cause of childhood disability in developed and developing countries, but the pathogenic mechanisms of CP development remain largely unknown. Autophagy is a highly conserved cellular self-digestion of damaged organelles and dysfunctional macromolecules. Growing evidence suggests that autophagy-related gene 5 (ATG5)-dependent autophagy is involved in neural development, neuronal differentiation, and neurological degenerative diseases. The aim of this study was to ana ...[more]

PMID: 29326554

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Project description: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 (p allele = 0.02 and 0.0004, p genotype = 0.044 and 0.0012, respectively). Subgroup analysis revealed a more significant association of rs1470612 (p allele = 0.004, p genotype = 0.0036) and rs2594972 (p allele = 0.0004, p genotype < 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 (p allele = 0.0024, p genotype = 0.008) and rs2594972 (p allele < 0.0001, p genotype = 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.

Dataset Information

A Variant of the Autophagy-Related 5 Gene Is Associated with Child Cerebral Palsy.

Publications

A Variant of the Autophagy-Related 5 Gene Is Associated with Child Cerebral Palsy.

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