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Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

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Rosa Woldegebriel, Jouni Kvist, Noora Andersson, Katrin Õunap, Karit Reinson, Monica H Wojcik, Emilia K Bijlsma, Mariëtte J V Hoffer, Monique M Ryan, Zornitza Stark, Maie Walsh, Inge Cuppen, Marie-Jose H van den Boogaard, Diana Bharucha-Goebel, Sandra Donkervoort, Sara Winchester, Roberto Zori, Carsten G Bönnemann, Reza Maroofian, Emer O'Connor & 8 more Henry Houlden, Fang Zhao, Olli Carpén, Matthew White, Jemeen Sreedharan, Murray Stewart, Emil Ylikallio, Henna Tyynismaa

Original languageEnglish
Pages (from-to)1426-1439
Number of pages14
JournalHuman Molecular Genetics
Issue number9
Early online date23 Mar 2020
E-pub ahead of print23 Mar 2020
Published3 Jun 2020

Bibliographical note

© The Author(s) 2020. Published by Oxford University Press.

King's Authors


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.

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