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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 473311.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism
Authors:Laumonnier, F.; Shoubridge, C.; Antar, C.; Nguyen, L. S.; Van Esch, H.; Kleefstra, T.; Briault, S.; Fryns, J. P.; Hamel, B.; Chelly, J.; Ropers, H.-H.; Ronce, N.; Blesson, S.; Moraine, C.; Gécz, J.; Raynaud, M.
Date of Publication (YYYY-MM-DD):2009-02-24
Title of Journal:Molecular Psychiatry
Journal Abbrev.:Mol Psychiatry
Start Page:1
End Page:10
Copyright:© 2009 Nature Publishing Group
Review Status:not specified
Audience:Experts Only
Abstract / Description:Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan–Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361*, in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan–Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.
Free Keywords:Autism; Mental retardation; Nonsense-mediated mRNA decay; Neuronal expression; X chromosome
Comment of the Author/Creator:email:
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:INSERM, U930, Tours, France
Université François-Rabelais, UMR 'Imaging and Brain', Tours, France
CNRS, ERL 3106, Tours, France
Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, SA, Australia
Centre Hospitalier Régional Universitaire de Tours, Tours, France
Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Centre Hospitalier Régional, Orléans, France
Institut Cochin, University Paris-Descartes, CNRS UMR 8104, INSERM U567, Paris, France
11School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
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