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Intron retention caused by a canonical splicing variant in SSR4-related congenital disorder of glycosylation

Journal of Human Genetics volume 70, pages 171–176 (2025)Cite this article

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Abstract

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.

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Data availability

Data available on request from the authors.

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Acknowledgements

This study was funded by National Natural Science Foundation of China (Grant No. 82471395), Shandong Provincial Natural Science Foundation (Grant No. ZR2023LSW020), Scientific Research Foundation of Qilu Hospital of Shandong University (Qingdao) (No.QDKY2021BS02), Qingdao Key Health Discipline Development Fund and Qingdao Clinical Research Center for Rare Diseases of Nervous System (22-3-7-lczx-3-nsh). We are grateful to the patient and his family for their participation.

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Author notes

  1. These authors contributed equally: Quanquan Wang, Guangyu Wang.

Authors and Affiliations

  1. Department of Neurology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China

    Quanquan Wang, Bing Liang, Chuanzhu Yan & Ling Li

  2. Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Guangyu Wang, Chuanzhu Yan & Pengfei Lin

  3. Department of Central Laboratory and Mitochondrial Medicine Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China

    Chen Zhang

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  1. Quanquan Wang
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  7. Ling Li
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Contributions

QQW contributed to patient evaluation, data acquisition, and manuscript drafting. GYW contributed to the functional analysis and manuscript drafting. BL and CZY contributed to the data acquisition. CZ contributed to the culture of fibroblasts. LL and PFL contributed to the study design, interpretation of the results, and revision of the manuscript. All authors approved the version of the article to be published.

Corresponding authors

Correspondence to Pengfei Lin or Ling Li.

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The authors declare no competing interests.

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This study was approved by the Ethics Committee of Qilu Hospital of Shandong University (Qingdao). Written informed consent for publication was obtained from all family members.

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Wang, Q., Wang, G., Liang, B. et al. Intron retention caused by a canonical splicing variant in SSR4-related congenital disorder of glycosylation. J Hum Genet 70, 171–176 (2025). https://doi.org/10.1038/s10038-024-01309-7

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