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

TitleDistinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.
Publication TypeJournal Article
Year of Publication2020
AuthorsWoldegebriel, R, Kvist, J, Andersson, N, Õunap, K, Reinson, K, Wojcik, MH, Bijlsma, EK, Hoffer, MJV, Ryan, MM, Stark, Z, Walsh, M, Cuppen, I, van den Boogaard, M-JH, Bharucha-Goebel, D, Donkervoort, S, Winchester, S, Zori, R, Bönnemann, CG, Maroofian, R, O'Connor, E, Houlden, H, Zhao, F, Carpén, O, White, M, Sreedharan, J, Stewart, M, Ylikallio, E, Tyynismaa, H
JournalHum Mol Genet
Volume29
Issue9
Pagination1426-1439
Date Published2020 Jun 03
ISSN1460-2083
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.

DOI10.1093/hmg/ddaa051
Alternate JournalHum. Mol. Genet.
PubMed ID32202298
PubMed Central IDPMC7297229
Grant ListMC_U105178939 / MR / Medical Research Council / United Kingdom
UM1 HG008900 / HG / NHGRI NIH HHS / United States