Novel NtA and LG1 Mutations in Agrin in a Single Patient Causes Congenital Myasthenic Syndrome

Aiping Wang; Yangyang Xiao; Peng Huang; Lingjuan Liu; Jie Xiong; Jian Li; Ding'an Mao; Liqun Liu

doi:10.3389/fneur.2020.00239

Novel NtA and LG1 Mutations in Agrin in a Single Patient Causes Congenital Myasthenic Syndrome

Front Neurol. 2020 Apr 9:11:239. doi: 10.3389/fneur.2020.00239. eCollection 2020.

Authors

Aiping Wang^{1

2}, Yangyang Xiao^{1

2}, Peng Huang^{1

2}, Lingjuan Liu^{1

2}, Jie Xiong^{1

2}, Jian Li^{1

2}, Ding'an Mao^{1

2}, Liqun Liu^{1

2}

Affiliations

¹ Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.
² Department of Pediatrics Neurology, Children's Medical Center, The Second Xiangya Hospital, Central South University, Changsha, China.

Abstract

Congenital myasthenic syndrome (CMS) is a group of genetic disorders of neuromuscular transmission that is characterized by muscle weakness. A mutation in the gene encoding agrin (AGRN) is a rare cause of CMS, and only a few families or isolated cases have been reported. We reported a pediatric proband exhibiting muscle weakness in the trunk and limbs with skeletal malformation and intellectual disability and performed whole-exome sequencing (WES) of the proband parent-offspring trio. Results revealed a new compound heterozygous mutation in AGRN: c.125A>C (p.Glu42Ala) in the N-terminal agrin domain (NtA) and c.4516G>A (p.Ala1506Thr) in the laminin G1 domain (LG1). Bioinformatic analysis predicted the mutation as possibly pathogenic. The new compound heterozygous mutation in AGRN may disrupt agrin's known function of bridging laminin and α-dystroglycan and undermine the formation and maintenance of the neuromuscular junction (NMJ) via both muscular and neural agrin pathways. It may also induce secondary peripheral neuropathy and skeletal malformation.

Keywords: AGRN; agrin; congenital myasthenic syndrome; missense mutation; whole-exome sequencing.

Publication types

Case Reports