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

Jianhua Xu; Lei Xia; Qing Shang; Jing Du; Dengna Zhu; Yangong Wang; Dan Bi; Juan Song; Caiyun Ma; Chao Gao; Xiaoli Zhang; Yanyan Sun; Liping Zhu; Xiaoyang Wang; Changlian Zhu; Qinghe Xing

doi:10.3389/fncel.2017.00407

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

Front Cell Neurosci. 2017 Dec 18:11:407. doi: 10.3389/fncel.2017.00407. eCollection 2017.

Authors

Jianhua Xu¹, Lei Xia², Qing Shang³, Jing Du¹, Dengna Zhu^{2

4}, Yangong Wang¹, Dan Bi², Juan Song², Caiyun Ma³, Chao Gao³, Xiaoli Zhang², Yanyan Sun², Liping Zhu⁵, Xiaoyang Wang⁶, Changlian Zhu^{2

7}, Qinghe Xing^{1

5}

Affiliations

¹ Institute of Biomedical Science and Children's Hospital, and Key Laboratory of Reproduction Regulation of the National Population and Family Planning Commission (NPFPC), Shanghai Institute of Planned Parenthood Research (SIPPR), IRD, Fudan University, Shanghai, China.
² Henan Key Laboratory of Child Brain Injury, Department of Pediatrics, The 3rd Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Department of Pediatrics, Henan Children's Hospital, Zhengzhou, China.
⁴ Child Rehabilitation Center, The 3rd Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Shanghai Center for Women and Children's Health, Shanghai, China.
⁶ Perinatal Center, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
⁷ Center for Brain Repair and Rehabilitation, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.

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, P_allele = 0.0005, P_genotype = 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, P_allele = 8.50e^-005, P_genotype = 1.57e^-004) and spastic quadriplegia (OR = 1.927, 95% CI = 1.533~2.421, P_allele = 7.35e^-008, P_genotype = 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.

Keywords: ATG5; ELISA; autophagy; cerebral palsy; polymorphisms; single nucleotide.