Woldegebriel, R;
Kvist, J;
Andersson, N;
Õunap, K;
Reinson, K;
Wojcik, MH;
Bijlsma, EK;
... Tyynismaa, H; + view all
(2020)
Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.
Human Molecular Genetics
, 29
(9)
pp. 1426-1439.
10.1093/hmg/ddaa051.
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Abstract
Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content dependent regulation of gene expression. For example all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease, and suggest mechanisms by which GANP defects might alter RNA metabolism.
| Type: | Article |
|---|---|
| Title: | Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddaa051 |
| Publisher version: | https://doi.org/10.1093/hmg/ddaa051 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com. |
| Keywords: | phenotype, nervous system disorders, gene expression, fibroblasts, genes, introns, intellectual disability, nuclear envelope, rna, messenger, skin fibroblasts, complex |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10098113 |
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