Functional analysis of fetal acetylcholine receptor in patients with Escobar syndrome

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19639
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Nagoya University
• Principal Investigator: Nakata Tomohiko 名古屋大学, 医学部附属病院, 助教 (40773065)
• Research Collaborator: NATSUME jun ; KIDOKORO hiroyuki ; OHNO kinji ; ITHO mikako ; MIZUNO seiji ; Engel Andrew G. ; Shen Xin-Ming
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: Escobar症候群 / CHRNG / 先天性筋無力症候群 / アセチルコリン受容体 / 先天性多発関節拘縮症 / 非致死型翼状片症候群

Outline of Final Research Achievements

The nonlethal Escobar syndrome is caused by mutation in the CHRNG gene, which encodes the fetal gamma subunit of the acetylcholine receptor. We performed sequencing of CHRNG for patients with multiple joint contractures and found heterozygous mutations including one missense mutation in three patients from two families. We described clinical features and studied functional analysis using culture cells for the missense mutation. Although the clinical features of Escobar syndrome are variable but the condition is characterized by pterygia, all three patients had very mild pterygia. We conducted expression experiments and channel functional analyses using culture cells. We revealed that the mutation cause the fetal fast channel syndrome with abnormally brief opening and activity of the channel.

Free Research Field

小児神経学

Academic Significance and Societal Importance of the Research Achievements

これまで成人型の骨格筋アセチルコリン受容体のチャネル動態異常による疾患は先天性筋無力症候群の一型として報告されているが、胎児型アセチルコリン受容体での報告はなかった。今回Escobar症候群3症例で同定した共通の遺伝子変異について胎児型アセチルコリン受容体の機能解析をおこない、発現量の低下とチャネル開口時間の異常によることを明らかにした。3症例は臨床像が類似しており、Escobar症候群で特徴的とされている翼状片が非常に軽微だった。先天性多発関節拘縮症には多数の原因があるが、翼状片が軽微であってもCHRNG変異を考える必要がある。