1. MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability
- Author
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Paul J. Lockhart, Kym M. Boycott, Koen L.I. van Gassen, Katrina M. Bell, Alicia Oshlack, Albena Jordanova, Rosa Woldegebriel, Esra Battaloglu, Marie José H. Van Den Boogaard, Maie Walsh, Monique M. Ryan, Manuela Tumiati, Taila Hartley, W. Ludo van der Pol, Yesim Parman, Mariia Shcherbii, Martine Tétreault, Ayse Candayan, Emil Ylikallio, Inge Cuppen, Pirjo Isohanni, Sarah L. Sawyer, Henna Tyynismaa, Liisa Kauppi, Derek Atkinson, Alejandro Estrada-Cuzcano, Tuula Lönnqvist, Zornitza Stark, Research Programs Unit, Research Programme for Molecular Neurology, University of Helsinki, Clinicum, Department of Neurosciences, Neurologian yksikkö, Medicum, Genome-Scale Biology (GSB) Research Program, Anu Wartiovaara / Principal Investigator, Children's Hospital, Lastenneurologian yksikkö, Genome Stability Group, Henna Tyynismaa / Principal Investigator, Department of Medical and Clinical Genetics, HUS Children and Adolescents, and HUS Neurocenter
- Subjects
0301 basic medicine ,Male ,Compound heterozygosity ,DISEASE ,3124 Neurology and psychiatry ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Intellectual disability ,GANP ,TRANSCRIPTION ,Nuclear protein ,Child ,Cells, Cultured ,Giant axonal neuropathy ,Genetics ,Medicine(all) ,TREX-2 COMPLEX ,Intracellular Signaling Peptides and Proteins ,MESSENGER-RNA EXPORT ,Pedigree ,GIANT AXONAL NEUROPATHY ,intellectual disability ,Child, Preschool ,DNA-REPAIR ,Female ,MUTATIONS CAUSE ,Charcot-Marie-Tooth neuropathy ,Adult ,Retrograde Degeneration ,Adolescent ,MCM3AP ,Clinical Neurology ,Biology ,03 medical and health sciences ,Young Adult ,Arts and Humanities (miscellaneous) ,Acetyltransferases ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,mRNA export ,DIFFERENTIATION-ASSOCIATED PROTEIN-1 ,3112 Neurosciences ,Heterozygote advantage ,Fibroblasts ,medicine.disease ,GENE ,030104 developmental biology ,Peripheral neuropathy ,Mutation ,Neurology (clinical) ,3111 Biomedicine ,Human medicine ,030217 neurology & neurosurgery - Abstract
Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.
- Published
- 2017