Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia
| العنوان: | Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia |
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| المؤلفون: | Kym M. Boycott, Lyndon Gallacher, Aziz Mhanni, Simon Sadedin, Xiaomin Dong, Kristin D. Kernohan, Arran McBride, Ismaël Alidou-D'Anjou, John Christodoulou, Zornitza Stark, Aren E Marshall, François Dragon, Samantha E Marin, Patrick Frosk, Marc R. Del Bigio, Sophie Sleiman |
| المصدر: | Human Molecular Genetics. 31:614-624 |
| بيانات النشر: | Oxford University Press (OUP), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Genetics, Dystonia, Saccharomyces cerevisiae Proteins, Neurodegeneration, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Saccharomyces cerevisiae, General Medicine, Biology, medicine.disease, Compound heterozygosity, Phenotype, Dystonic Disorders, medicine, Humans, Small nucleolar RNA, RRNA processing, Molecular Biology, Genetics (clinical), Exome sequencing, Ribonucleoprotein |
| الوصف: | SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition. |
| تدمد: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddab247 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6876a2f473d6b0271228df3c24e60761 https://doi.org/10.1093/hmg/ddab247 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6876a2f473d6b0271228df3c24e60761 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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| DOI: | 10.1093/hmg/ddab247 |