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

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.

• Authors: 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, Henry Houlden, Fang Zhao, Olli Carpén, Matthew White, Jemeen Sreedharan, Murray Stewart, Emil Ylikallio, Henna Tyynismaa
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 29 Issue 9 Pg. 1426-1439 (06 03 2020) ISSN: 1460-2083 [Electronic] England
• PMID: 32202298 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press.

Chemical References

• ATXN7L3B protein, human
• Antigens, Surface
• Flavoproteins
• Glycoproteins
• Intracellular Signaling Peptides and Proteins
• Nuclear Proteins
• PCID2 protein, human
• Phosphoproteins
• RNA, Messenger
• SAGA-1 protein, human
• Transcription Factors
• Acetyltransferases
• MCM3AP protein, human
• Exodeoxyribonucleases
• TREX2 protein, human
• FIG4 protein, human
• Phosphoric Monoester Hydrolases

Topics

• Acetyltransferases (chemistry, genetics, ultrastructure)
• Age of Onset
• Antigens, Surface (genetics)
• Cell Nucleus (genetics)
• Child
• Child, Preschool
• Exodeoxyribonucleases (genetics)
• Female
• Flavoproteins (genetics)
• Gene Expression Regulation (genetics)
• Glycoproteins (genetics)
• Humans
• Intellectual Disability (genetics, pathology)
• Intracellular Signaling Peptides and Proteins (chemistry, genetics)
• Introns (genetics)
• Male
• Nervous System Diseases (genetics, pathology)
• Nuclear Proteins (genetics, ultrastructure)
• Peripheral Nervous System Diseases (genetics, pathology)
• Phenotype
• Phosphoproteins (genetics)
• Phosphoric Monoester Hydrolases (genetics)
• Protein Conformation
• RNA Transport (genetics)
• RNA, Messenger (genetics)
• Transcription Factors (genetics)