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Hum Mol Genet. 2020 Mar 23. pii: ddaa051. doi: 10.1093/hmg/ddaa051. [Epub ahead of print]

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

Author information

1
Stem Cells and Metabolism Research Program, Research Programs Unit, University of Helsinki, 00290 Helsinki, Finland.
2
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
3
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
4
Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.
5
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
6
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
7
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
8
Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
9
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
10
Murdoch Children's Research Institute, Melbourne, Victoria, 3052, Australia.
11
Royal Children's Hospital, Melbourne, Victoria, 3052, Australia.
12
Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, 3052, Australia.
13
Department of Pediatric Neurology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
14
Brain Centre Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Centre Utrecht, 3508 Utrecht, The Netherlands.
15
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA.
16
Division of Neurology, Children's National Health System, Washington, DC, USA.
17
Child Neurology Center of Northwest Florida, Pensacola, FL, USA.
18
Division of Genetics and Metabolism, University of Florida, Gainesville, FL, USA.
19
Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
20
Department of Pathology and Genetics, HUSLAB Laboratories, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
21
MRC Laboratory of Molecular Biology, Francis Crick Ave, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
22
Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
23
Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
24
Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.

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.

PMID:
32202298
DOI:
10.1093/hmg/ddaa051

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