Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape
Abstract Morquio B disease (MBD) is an ultra-rare lysosomal storage disease, which represents the relatively mild form of GLB1-associated disorders. In this article, we present the unique case of “pure” MBD associated with an insertion of the mobile genetic element from the class of retrotransposons...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-07-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-022-00315-y |
| _version_ | 1818162618007814144 |
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| author | Igor Bychkov Antonina Kuznetsova Galina Baydakova Leonid Gorobets Vladimir Kenis Alena Dimitrieva Alexandra Filatova Vyacheslav Tabakov Mikhail Skoblov Ekaterina Zakharova |
| author_facet | Igor Bychkov Antonina Kuznetsova Galina Baydakova Leonid Gorobets Vladimir Kenis Alena Dimitrieva Alexandra Filatova Vyacheslav Tabakov Mikhail Skoblov Ekaterina Zakharova |
| author_sort | Igor Bychkov |
| collection | DOAJ |
| description | Abstract Morquio B disease (MBD) is an ultra-rare lysosomal storage disease, which represents the relatively mild form of GLB1-associated disorders. In this article, we present the unique case of “pure” MBD associated with an insertion of the mobile genetic element from the class of retrotransposons. Using whole-genome sequencing (WGS), we identified an integration of the processed pseudogene NPM1 deep in the intron 5 of GLB1. The patient’s mRNA analysis and the detailed functional analysis revealed the underlying molecular genetic mechanism of pathogenesis, which is an alteration of the GLB1 normal splicing. By co-expression of minigenes and antisense splice-modulating oligonucleotides (ASMOs), we demonstrated that pseudogene-derived splicing regulatory motifs contributed to an activation of the cryptic exon located 36 bp upstream of the integration site. Blocking the cryptic exon with ASMOs incorporated in the modified U7 small nuclear RNA (modU7snRNA) almost completely restored the wild-type splicing in the model cell line, that could be further extended toward the personalized genetic therapy. To our knowledge, this is the second reported case of the processed pseudogene insertion for monogenic disorders. Our data emphasizes the unique role of WGS in identification of such rare and probably underrepresented in literature types of disease-associated genetic variants. |
| first_indexed | 2024-12-11T16:36:31Z |
| format | Article |
| id | doaj.art-e21593aacde74b53b521f3ae1e5957fb |
| institution | Directory Open Access Journal |
| issn | 2056-7944 |
| language | English |
| last_indexed | 2024-12-11T16:36:31Z |
| publishDate | 2022-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj.art-e21593aacde74b53b521f3ae1e5957fb2022-12-22T00:58:27ZengNature Portfolionpj Genomic Medicine2056-79442022-07-01711610.1038/s41525-022-00315-yProcessed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscapeIgor Bychkov0Antonina Kuznetsova1Galina Baydakova2Leonid Gorobets3Vladimir Kenis4Alena Dimitrieva5Alexandra Filatova6Vyacheslav Tabakov7Mikhail Skoblov8Ekaterina Zakharova9Research Centre for Medical GeneticsResearch Centre for Medical GeneticsResearch Centre for Medical GeneticsClinical and Diagnostic Center “Zdorovoe detstvo”H. Turner National Medical Research Centre for Children’s Orthopedics and Trauma SurgeryH. Turner National Medical Research Centre for Children’s Orthopedics and Trauma SurgeryResearch Centre for Medical GeneticsResearch Centre for Medical GeneticsResearch Centre for Medical GeneticsResearch Centre for Medical GeneticsAbstract Morquio B disease (MBD) is an ultra-rare lysosomal storage disease, which represents the relatively mild form of GLB1-associated disorders. In this article, we present the unique case of “pure” MBD associated with an insertion of the mobile genetic element from the class of retrotransposons. Using whole-genome sequencing (WGS), we identified an integration of the processed pseudogene NPM1 deep in the intron 5 of GLB1. The patient’s mRNA analysis and the detailed functional analysis revealed the underlying molecular genetic mechanism of pathogenesis, which is an alteration of the GLB1 normal splicing. By co-expression of minigenes and antisense splice-modulating oligonucleotides (ASMOs), we demonstrated that pseudogene-derived splicing regulatory motifs contributed to an activation of the cryptic exon located 36 bp upstream of the integration site. Blocking the cryptic exon with ASMOs incorporated in the modified U7 small nuclear RNA (modU7snRNA) almost completely restored the wild-type splicing in the model cell line, that could be further extended toward the personalized genetic therapy. To our knowledge, this is the second reported case of the processed pseudogene insertion for monogenic disorders. Our data emphasizes the unique role of WGS in identification of such rare and probably underrepresented in literature types of disease-associated genetic variants.https://doi.org/10.1038/s41525-022-00315-y |
| spellingShingle | Igor Bychkov Antonina Kuznetsova Galina Baydakova Leonid Gorobets Vladimir Kenis Alena Dimitrieva Alexandra Filatova Vyacheslav Tabakov Mikhail Skoblov Ekaterina Zakharova Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape npj Genomic Medicine |
| title | Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape |
| title_full | Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape |
| title_fullStr | Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape |
| title_full_unstemmed | Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape |
| title_short | Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape |
| title_sort | processed pseudogene insertion in glb1 causes morquio b disease by altering intronic splicing regulatory landscape |
| url | https://doi.org/10.1038/s41525-022-00315-y |
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