Chrnd, encoding the delta subunit of the acetylcholine receptor (AChR), is crucial for normal neuromuscular signal transmission at the neuromuscular junction (NMJ) [1,3]. The AChR plays a vital role in the process of converting chemical signals into electrical signals in muscle cells, a key step in muscle contraction. Mutations in Chrnd can disrupt this process, leading to various neuromuscular disorders [1,3].

Mutations in the Chrnd gene have been associated with congenital myasthenic syndromes (CMS) [1,2,3,5]. For example, a patient with CMS was found to have a heterozygous 2.2 kb microdeletion disrupting the Chrnd gene and a novel point mutation in the long cytoplasmic loop (CHRND E381K). Functional studies in HEK 293 cells showed that the mutated receptor had severely reduced cluster formation with rapsyn compared to the wild-type receptor, suggesting that Chrnd mutations can cause CMS by impairing AChR-rapsyn co-clustering [3]. Additionally, two novel mutations in Chrnd (NM_000751.2: c.1006C>T p.(Arg336Ter) and NM_000751.2:c.973_975delGTG p.(Val325del)) were reported in a case of lethal multiple pterygium syndrome (LMPS), expanding the spectrum of genetic variants associated with this rare disease [4].

In conclusion, Chrnd is essential for proper neuromuscular function. Research on Chrnd mutations in model systems, such as cell lines, has revealed its role in CMS and LMPS. Understanding Chrnd's function through these studies can potentially lead to better diagnostic and therapeutic strategies for these neuromuscular disorders.

References:

1. Ohno, Kinji, Ohkawara, Bisei, Shen, Xin-Ming, Selcen, Duygu, Engel, Andrew G. 2023. Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review. In International journal of molecular sciences, 24, . doi:10.3390/ijms24043730. https://pubmed.ncbi.nlm.nih.gov/36835142/

2. Kondo, Hidehito, Tsuji, Yukiko, Lee, Tomoko, Saito, Yoshihiko, Nishino, Ichizo. . Severe congenital myasthenic syndrome with novel variants in the CHRND gene. In Pediatrics international : official journal of the Japan Pediatric Society, 64, e15342. doi:10.1111/ped.15342. https://pubmed.ncbi.nlm.nih.gov/36370373/

3. Müller, Juliane S, Baumeister, Sarah K, Schara, Ulrike, Lochmüller, Hanns, Abicht, Angela. 2006. CHRND mutation causes a congenital myasthenic syndrome by impairing co-clustering of the acetylcholine receptor with rapsyn. In Brain : a journal of neurology, 129, 2784-93. doi:. https://pubmed.ncbi.nlm.nih.gov/16916845/

4. Chen, Caiyuan, Han, Jin, Xue, Jiaxin, Li, Fucheng, Li, Dongzhi. 2023. Case Report: Early diagnosis of lethal multiple pterygium syndrome with micrognathia: Two novel mutations in the CHRND gene. In Frontiers in genetics, 14, 1005624. doi:10.3389/fgene.2023.1005624. https://pubmed.ncbi.nlm.nih.gov/36733345/

5. Theuriet, Julian, Masingue, Marion, Behin, Anthony, Stojkovic, Tanya, Eymard, Bruno. . Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis. In Brain : a journal of neurology, 147, 3849-3862. doi:10.1093/brain/awae124. https://pubmed.ncbi.nlm.nih.gov/38696726/