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.
References
Verheijen J, Tahata S, Kozicz T, Witters P, Morava E. Therapeutic approaches in congenital disorders of glycosylation (CDG) involving N-linked glycosylation: an update. Genet Med. 2020;22:268–79. https://doi.org/10.1038/s41436-019-0647-2.
ArticlePubMedGoogle Scholar
Ondruskova N, Cechova A, Hansikova H, Honzik T, Jaeken J. Congenital disorders of glycosylation: still “hot” in 2020. Biochim Biophys Acta Gen Subj. 2021;1865:129751. https://doi.org/10.1016/j.bbagen.2020.129751.
ArticlePubMedGoogle Scholar
Losfeld ME, Ng BG, Kircher M, Buckingham KJ, Turner EH, Eroshkin A. et al. A new congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex. Hum Mol Genet. 2014;23:1602–5. https://doi.org/10.1093/hmg/ddt550.
ArticlePubMedGoogle Scholar
Wang J, Gou X, Wang X, Zhang J, Zhao N, Wang X. Case Report: the novel hemizygous mutation in the SSR4 gene caused congenital disorder of glycosylation type iy: a case study and literature review. Front Genet. 2022;13:955732. https://doi.org/10.3389/fgene.2022.955732.
ArticlePubMedPubMed CentralGoogle Scholar
Johnsen C, Tabatadze N, Radenkovic S, Botzo G, Kuschel B, Melikishvili G. et al. SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: review of 22 affected individuals including the first adult patient. Mol Genet Metab. 2024;142:108477. https://doi.org/10.1016/j.ymgme.2024.108477.
ArticlePubMedGoogle Scholar
Ng BG, Raymond K, Kircher M, Buckingham KJ, Wood T, Shendure J. et al. Expanding the molecular and clinical phenotype of SSR4-CDG. Hum Mutat. 2015;36:1048–51. https://doi.org/10.1002/humu.22856.
ArticlePubMedPubMed CentralGoogle Scholar
Castiglioni C, Feillet F, Barnerias C, Wiedemann A, Muchart J, Cortes F. et al. Expanding the phenotype of X-linked SSR4-CDG: connective tissue implications. Hum Mutat. 2021;42:142–9. https://doi.org/10.1002/humu.24151.
ArticlePubMedGoogle Scholar
Medrano C, Vega A, Navarrete R, Ecay MJ, Calvo R, Pascual SI. et al. Clinical and molecular diagnosis of nonphosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain. Clin Genet. 2019;95:615–26. https://doi.org/10.1111/cge.13508.
ArticlePubMedGoogle Scholar
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. https://doi.org/10.1038/gim.2015.30.
ArticlePubMedPubMed CentralGoogle Scholar
Biesecker LG, Byrne AB, Harrison SM, Pesaran T, Schäffer AA, Shirts BH. ClinGen Sequence Variant Interpretation Working Group.et al. ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification. Am J Hum Genet. 2024;111:24–38. https://doi.org/10.1016/j.ajhg.2023.11.009.
ArticlePubMedGoogle Scholar
Sheth N, Roca X, Hastings ML, Roeder T, Krainer AR, Sachidanandam R. Comprehensive splice-site analysis using comparative genomics. Nucleic Acids Res. 2006;34:3955–67. https://doi.org/10.1093/nar/gkl556.
ArticlePubMedPubMed CentralGoogle Scholar
Lin JH, Tang XY, Boulling A, Zou WB, Masson E, Fichou Y. et al. First estimate of the scale of canonical 5*'* splice site GT>GC variants capable of generating wild-type transcripts. Hum Mutat. 2019;40:1856–73. https://doi.org/10.1002/humu.23821.
ArticlePubMedGoogle Scholar
Lv Y, Gu J, Qiu H, Li H, Zhang Z, Yin S. et al. Whole-exome sequencing identifies a donor splice-site variant in SMPX that causes rare X-linked congenital deafness. Mol Genet Genom Med. 2019;7:e967. https://doi.org/10.1002/mgg3.967.
ArticleGoogle Scholar
Sakamoto O, Ohura T, Katsushima Y, Fujiwara I, Ogawa E, Miyabayashi S. et al. A novel intronic mutation of the TAZ (G4.5) gene in a patient with Barth syndrome: creation of a 5*'* splice donor site with variant GC consensus and elongation of the upstream exon. Hum Genet. 2001;109:559–63. https://doi.org/10.1007/s00439-001-0612-3.
ArticlePubMedGoogle Scholar
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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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These authors contributed equally: Quanquan Wang, Guangyu Wang.
Authors and Affiliations
Department of Neurology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China
Quanquan Wang, Bing Liang, Chuanzhu Yan & Ling Li
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
Department of Central Laboratory and Mitochondrial Medicine Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China
Chen Zhang
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Quanquan Wang
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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.
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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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Supplementary information
Supplementary table 1 Summary of clinical features and frequencies in SSR4-CDG.
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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 (2024). https://doi.org/10.1038/s10038-024-01309-7
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Received:31 May 2024
Revised:08 November 2024
Accepted:30 November 2024
Published:10 December 2024
DOI:https://doi.org/10.1038/s10038-024-01309-7
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