Wang Quanquan, Wang Guangyu, Liang Bing, Zhang Chen, Yan Chuanzhu, Lin Pengfei, Li Ling
Department of Neurology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China.
Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China.
J Hum Genet. 2025 Mar;70(3):171-176. doi: 10.1038/s10038-024-01309-7. Epub 2024 Dec 10.
Congenital disorder of glycosylation type Iy (CDG-Iy) is an X-linked monogenic inherited disease caused by variants in the SSR4 gene. To date, a total of 11 variants have been identified in 14 CDG-Iy patients. Our study identified a novel canonical splicing variant, c.67+2T>C, in the SSR4 gene (according to the transcript NM_006280.3) in a Chinese CDG-Iy family. Functional analysis revealed that the c.67+2T>C variant induced the retention of the first 46 bp of intron 1 via the recognition of the downstream GC dinucleotide as a non-canonical cryptic donor splice site. This aberrant mRNA splicing resulted in the occurrence of a premature termination codon, triggered nonsense-mediated mRNA decay, and decreased the SSR4 gene expression. Our study is the first to identify aberrant mRNA processing in SSR4-related CDG-Iy and further emphasizes the activation of the non-canonical GC donor splice site in aberrant mRNA processing caused by splicing variants.
先天性糖基化障碍Iy型（CDG-Iy）是一种由SSR4基因变异引起的X连锁单基因遗传病。迄今为止，在14例CDG-Iy患者中总共鉴定出11种变异。我们的研究在中国一个CDG-Iy家系中，于SSR4基因（根据转录本NM_006280.3）中鉴定出一种新的典型剪接变异c.67+2T>C。功能分析显示，c.67+2T>C变异通过将下游GC二核苷酸识别为非典型隐蔽供体剪接位点，导致内含子1的前46bp保留。这种异常的mRNA剪接导致了提前终止密码子的出现，引发了无义介导的mRNA降解，并降低了SSR4基因的表达。我们的研究首次鉴定出与SSR4相关的CDG-Iy中的异常mRNA加工，并进一步强调了剪接变异导致的异常mRNA加工中非典型GC供体剪接位点的激活。
