@article{f43e5ca34a0d4331bbd9b5d98042fd0b,
title = "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability",
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.",
keywords = "Charcot-Marie-Tooth neuropathy, GANP, intellectual disability, MCM3AP, mRNA export",
author = "Emil Ylikallio and Rosa Woldegebriel and Manuela Tumiati and Pirjo Isohanni and Ryan, {Monique M.} and Zornitza Stark and Maie Walsh and Sawyer, {Sarah L.} and Bell, {Katrina M.} and Alicia Oshlack and Lockhart, {Paul J.} and Mariia Shcherbii and Alejandro Estrada-Cuzcano and Derek Atkinson and Taila Hartley and Martine Tetreault and Inge Cuppen and {Van Der Pol}, {W. Ludo} and Ayse Candayan and Esra Battaloglu and Yesim Parman and {Van Gassen}, {Koen L.I.} and {Van Den Boogaard}, {Marie Jos{\'e} H.} and Boycott, {Kym M.} and Liisa Kauppi and Albena Jordanova and Tuula L{\"o}nnqvist and Henna Tyynismaa",
note = "Funding Information: Patient A{\textquoteright}s sequencing was completed as part of a study funded and supported by the Melbourne Genomic Health Alliance. This work was supported in part by the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. Whole exome sequencing for Family C was performed as part of the Care4Rare Canada Consortium, funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children{\textquoteright}s Hospital of Eastern Ontario Foundation. Analysis of the Turkish family is supported partially by Bogazici University Research Fund Grant Number 14B01D5. The following funding sources are also gratefully acknowledged: Academy of Finland (H.T., E.Y., L.K.), Sigrid Juselius Foundation (H.T., L.K.), University of Helsinki (H.T., E.Y., M.T.), Biocentrum Helsinki (L.K.), Finska l{\"a}kares{\"a}llskapet (E.Y.), Helsinki University Hospital (E.Y.), Foundation for Pediatric Research (P.I.), Fund for Scientific Research-Flanders (FWO) (A.J.), University of Antwerp (A.J.), Belgium Association for Neuromuscular Disorders (ABMM) (A.J.), research fellowships from the Fund for Scientific Research-Flanders (FWO) (D.A.,A.E.-C), NHMRC Career Development Fellowship (GNT1032364) (P.J.L). Publisher Copyright: {\textcopyright} The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2017",
month = aug,
day = "1",
doi = "10.1093/brain/awx138",
language = "English",
volume = "140",
pages = "2093--2103",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "8",
}