A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development.

Autor: Rahikkala E; Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. elisa.rahikkala@ppshp.fi.; Institute of Biomedicine, University of Turku, Turku, Finland. elisa.rahikkala@ppshp.fi., Urpa L; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Ghimire B; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Topa H; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Kurki MI; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Koskela M; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Airavaara M; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Hämäläinen E; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Pylkäs K; Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, NordLab Oulu, Oulu, Finland., Körkkö J; Center for Intellectual Disability Care, Oulu University Hospital, Oulu, Finland., Savolainen H; Center for Intellectual Disability Care, Oulu University Hospital, Oulu, Finland., Suoranta A; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Bertoli-Avella A; Centogene GmbH, 18055, Rostock, Germany., Rolfs A; Centogene GmbH, 18055, Rostock, Germany.; Medical Faculty, University of Rostock, Rostock, Germany., Mattila P; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Daly M; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Palotie A; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Pietiläinen O; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Moilanen J; Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland., Kuismin O; Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2022 May; Vol. 30 (5), pp. 619-627. Date of Electronic Publication: 2022 Jan 28.
DOI: 10.1038/s41431-022-01046-5
Abstrakt: Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development.
(© 2022. The Author(s).)
Databáze: MEDLINE
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